Triazolopyridine compounds, compositions and methods of use thereof

ABSTRACT

Compounds of Formula 0, Formula I and Formula II and methods of use as Janus kinase inhibitors are described herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of International Application No.PCT/CN2014/085276, filed Aug. 27, 2014, which claims the benefit ofpriority to U.S. Provisional Application Ser. No. 61/874,038, filed Sep.5, 2013, each of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The field of the invention pertains to compounds of Formulas 0, I andII, and subformulas thereof, that are inhibitors of a Janus kinase, suchas JAK1, as well as compositions containing these compounds, and methodsof use including, but not limited to, diagnosis or treatment of patientssuffering from a condition responsive to the inhibition of a JAK kinase.

BACKGROUND OF INVENTION

Cytokine pathways mediate a broad range of biological functions,including many aspects of inflammation and immunity. Janus kinases(JAK), including JAK1, JAK2, JAK3 and TYK2, are cytoplasmic proteinkinases that associate with type I and type II cytokine receptors andregulate cytokine signal transduction. Cytokine engagement with cognatereceptors triggers activation of receptor associated JAKs and this leadsto JAK-mediated tyrosine phosphorylation of signal transducer andactivator of transcription (STAT) proteins and ultimatelytranscriptional activation of specific gene sets (Schindler et al.,2007, J. Biol. Chem. 282: 20059-63). JAK1, JAK2 and TYK2 exhibit broadpatterns of gene expression, while JAK3 expression is limited toleukocytes. Cytokine receptors are typically functional as heterodimers,and as a result, more than one type of JAK kinase is usually associatedwith cytokine receptor complexes. The specific JAKs associated withdifferent cytokine receptor complexes have been determined in many casesthrough genetic studies and corroborated by other experimental evidence.Exemplary therapeutic benefits of the inhibition of JAK enzymes arediscussed, for example, in International Application No. WO 2013/014567.

JAK1 was initially identified in a screen for novel kinases (Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607). Genetic andbiochemical studies have shown that JAK1 is functionally and physicallyassociated with the type I interferon (e.g., IFNalpha), type IIinterferon (e.g., IFNgamma), and IL-2 and IL-6 cytokine receptorcomplexes (Kisseleva et al., 2002, Gene 285:1-24; Levy et al., 2005,Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). JAK1 knockout mice die perinatally due to defectsin LIF receptor signaling (Kisseleva et al., 2002, Gene 285:1-24; O'Sheaet al., 2002, Cell, 109 (suppl.): S121-S131). Characterization oftissues derived from JAK1 knockout mice demonstrated critical roles forthis kinase in the IFN, IL-10, IL-2/IL-4 and IL-6 pathways. A humanizedmonoclonal antibody targeting the IL-6 pathway (Tocilizumab) wasrecently approved by the European Commission for the treatment ofmoderate-to-severe rheumatoid arthritis (Scheinecker et al., 2009, Nat.Rev. Drug Discov. 8:273-274).

CD4 T cells play an important role in asthma pathogenesis through theproduction of TH2 cytokines within the lung, including IL-4, IL-9 andIL-13 (Cohn et al., 2004, Annu. Rev. Immunol. 22:789-815). IL-4 andIL-13 induce increased mucus production, recruitment of eosinophils tothe lung, and increased production of IgE (Kasaian et al., 2008,Biochem. Pharmacol. 76(2): 147-155). IL-9 leads to mast cell activation,which exacerbates the asthma symptoms (Kearley et al., 2011, Am. J.Resp. Crit. Care Med., 183(7): 865-875). The IL-4Rα chain activates JAK1and binds to either IL-4 or IL-13 when combined with the common gammachain or the IL-13Rα1 chain respectively (Pernis et al., 2002, J. Clin.Invest. 109(10):1279-1283). The common gamma chain can also combine withIL-9Rα to bind to IL-9, and IL-9Rα activates JAK1 as well (Demoulin etal., 1996, Mol. Cell Biol. 16(9):4710-4716). While the common gammachain activates JAK3, it has been shown that JAK1 is dominant over JAK3,and inhibition of JAK1 is sufficient to inactivate signaling through thecommon gamma chain despite JAK3 activity (Haan et al., 2011, Chem. Biol.18(3):314-323). Inhibition of IL-4, IL-13 and IL-9 signaling by blockingthe JAK/STAT signaling pathway can alleviate asthmatic symptoms inpre-clinical lung inflammation models (Mathew et al., 2001, J. Exp. Med.193(9): 1087-1096; Kudlacz et. al., 2008, Eur. J. Pharmacol. 582(1-3):154-161).

Biochemical and genetic studies have shown an association between JAK2and single-chain (e.g., EPO), IL-3 and interferon gamma cytokinereceptor families (Kisseleva et al., 2002, Gene 285:1-24; Levy et al.,2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell,109 (suppl.): S121-S131). Consistent with this, JAK2 knockout mice dieof anemia (O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Kinaseactivating mutations in JAK2 (e.g., JAK2 V617F) are associated withmyeloproliferative disorders in humans.

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is critical for lymphoid celldevelopment and proliferation and mutations in JAK3 result in severecombined immunodeficiency (SCID) (O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). Based on its role in regulating lymphocytes, JAK3and JAK3-mediated pathways have been targeted for immunosuppressiveindications (e.g., transplantation rejection and rheumatoid arthritis)(Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelianet al., 2003, Science 302: 875-878).

TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6,IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al.,2002, Gene 285:1-24; Watford, W. T. & O'Shea, J. J., 2006, Immunity25:695-697). Consistent with this, primary cells derived from a TYK2deficient human are defective in type I interferon, IL-6, IL-10, IL-12and IL-23 signaling. A fully human monoclonal antibody targeting theshared p40 subunit of the IL-12 and IL-23 cytokines (Ustekinumab) wasrecently approved by the European Commission for the treatment ofmoderate-to-severe plaque psoriasis (Krueger et al., 2007, N. Engl. J.Med. 356:580-92; Reich et al., 2009, Nat. Rev. Drug Discov. 8:355-356).In addition, an antibody targeting the IL-12 and IL-23 pathwaysunderwent clinical trials for treating Crohn's Disease (Mannon et al.,2004, N. Engl. J. Med. 351:2069-79).

There exists a need in the art for additional or alternative treatmentsof conditions mediated by JAK kinases, such as those described above.

SUMMARY OF INVENTION

One aspect of the invention includes a compound of Formula 0:

stereoisomers and salts thereof, wherein Ar¹, R^(1a), R²-R⁵, X and n aredefined herein.

One other aspect of the invention includes a compound of Formula I:

stereoisomers and salts thereof, wherein Ar¹, R^(1a), R²-R⁵, X and n aredefined herein.

Another aspect of the present invention includes a compound of FormulaII:

and stereoisomers and salts thereof, wherein Q¹ and Q² are definedherein.

Also provided herein are compounds of Formulas Ia, Ib, Ic, Id, Ie, If,and Ig, as described below.

Another aspect includes a pharmaceutical composition that comprises acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or acompound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, and apharmaceutically acceptable carrier, diluent or excipient.

Another aspect includes use of a compound of Formula 0, I, Ia, Ib, Ic,Id, Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1to 2-486 or 3-1, for use in therapy, such as the treatment of aninflammatory disease or cancer.

Another aspect includes a method of preventing, treating or lesseningthe severity of a disease or condition responsive to the inhibition of aJanus kinase, such as JAK1 kinase, in a patient. The method can compriseadministering to the patient a therapeutically effective amount of acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or acompound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1.

Another aspect includes the use of a compound of Formula 0, I, Ia, Ib,Ic, Id, Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303,2-1 to 2-486 or 3-1, in the manufacture of a medicament for thetreatment of a disease responsive to the inhibition of a Janus kinase,such as JAK1 kinase.

Another aspect includes a kit for treating a disease or disorderresponsive to the inhibition of a Janus kinase, such as JAK1 kinase. Thekit can comprise a first pharmaceutical composition comprising acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or acompound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, andinstructions for use.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Halogen” or “halo” refers to F, Cl, Br or I. Additionally, terms suchas “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted. In one example, the alkyl radical is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the alkyl radical isC₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, orC₁-C₃. C₀ alkyl refers to a bond. Examples of alkyl groups includemethyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl. In someembodiments, substituents for “optionally substituted alkyls” includeone to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂,NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl,butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo,trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino,SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein thealkyl, phenyl and heterocyclic portions thereof may be optionallysubstituted, such as by one to four instances of substituents selectedfrom this same list.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon double bond, wherein the alkenyl radical may be optionallysubstituted, and includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. In oneexample, the alkenyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethenyl or vinyl(—CH═CH₂), prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂),2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl. In some embodiments,substituents for “optionally substituted alkenyls” include one to fourinstances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃,C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl,isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon,triple bond, wherein the alkynyl radical may be optionally substituted.In one example, the alkynyl radical is two to eighteen carbon atoms(C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀,C₂-C₈, C₂-C₆ or C₂-C₃. Examples include, but are not limited to, ethynyl(—CCH), prop-1-ynyl (—C≡CH₃), prop-2-ynyl (propargyl, —CH₂C≡CH),but-1-ynyl, but-2-ynyl and but-3-ynyl. In some embodiments, substituentsfor “optionally substituted alkynyls” include one to four instances ofF, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclicportions thereof may be optionally substituted, such as by one to fourinstances of substituents selected from this same list.

“Alkylene” refers to a saturated, branched or straight chain hydrocarbongroup having two monovalent radical centers derived by the removal oftwo hydrogen atoms from the same or two different carbon atoms of aparent alkane. In one example, the divalent alkylene group is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the divalent alkylenegroup is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅,C₁-C₄, or C₁-C₃. The group C₀ alkylene refers to a bond. Examplealkylene groups include methylene (—CH₂—), 1,1-ethyl (—CH(CH₃)—),(1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—), 2,2-propyl(—C(CH₃)₂—), 1,2-propyl (—CH(CH₃)CH₂—), 1,3-propyl (—CH₂CH₂CH₂—),1,1-dimethyleth-1,2-yl (—C(CH₃)₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like.

“Alkenylene” refers to an unsaturated, branched or straight chainhydrocarbon group having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkene. In one example, the alkenylene group is two toeighteen carbon atoms (C₂-C₁₈). In other examples, the alkenylene groupis C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. An exemplary alkenylene groupis 1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chainhydrocarbon group having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkyne. In one example, the alkynylene radical is twoto eighteen carbon atoms (C₂-C₁₈). In other examples, the alkynyleneradical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Example alkynyleneradicals include: acetylene (—C≡C—), propargyl (—CH₂C≡C—), and4-pentynyl (—CH₂CH₂CH₂C≡C—).

The term “heteroalkyl” refers to a straight or branched chain monovalenthydrocarbon radical, consisting of the stated number of carbon atoms,or, if none are stated, up to 18 carbon atoms, and from one to fiveheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms can optionally be oxidized and thenitrogen heteroatom can optionally be quaternized. In some embodiments,the heteroatom is selected from O, N and S, wherein the nitrogen andsulfur atoms can optionally be oxidized and the nitrogen heteroatom canoptionally be quaternized. The heteroatom(s) can be placed at anyinterior position of the heteroalkyl group, including the position atwhich the alkyl group is attached to the remainder of the molecule(e.g., —O—CH₂—CH₃). Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃,—Si(CH₃)₃ and —CH₂—CH═N—OCH₃. Up to two heteroatoms can be consecutive,such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Heteroalkylgroups can be optionally substituted. In some embodiments, substituentsfor “optionally substituted heteroalkyls” include one to four instancesof F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃,COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl,cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

“Amidine” means the group —C(NH)—NHR in which R is hydrogen, alkyl,cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryland heterocyclyl groups are as defined herein. A particular amidine isthe group —NH—C(NH)—NH₂.

“Amino” means primary (i.e., —NH₂), secondary (i.e., —NRH) and tertiary(i.e., —NRR) amines, that are optionally substituted, in which R isalkyl, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, cycloalkyl,aryl and heterocyclyl groups are as defined herein. Particular secondaryand tertiary amines are alkylamine, dialkylamine, arylamine,diarylamine, aralkylamine and diaralkylamine, wherein the alkyl and arylportions can be optionally substituted. Particular secondary andtertiary amines are methylamine, ethylamine, propylamine,isopropylamine, phenyl amine, benzylamine, dimethylamine, diethylamine,dipropylamine and diisopropylamine.

“Aryl” refers to a carbocyclic aromatic group, whether or not fused toone or more groups, having the number of carbon atoms designated, or ifno number is designated, up to 14 carbon atoms. One example includesaryl groups having 6-14 carbon atoms. Another example includes arylgroups having 6-10 carbon atoms. Examples of aryl groups include phenyl,naphthyl, biphenyl, phenanthrenyl, naphthacenyl,1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, andthe like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A., ed.)13^(th) ed. Table 7-2 [1985]). A particular aryl is phenyl. Substitutedphenyl or substituted aryl means a phenyl group or aryl groupsubstituted with one, two, three, four or five sub stituents, forexample, 1-2, 1-3 or 1-4 substituents, such as chosen from groupsspecified herein (see “optionally substituted” definition), such as F,Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclicportions thereof may be optionally substituted, such as by one to fourinstances of substituents selected from this same list. Examples of theterm “substituted phenyl” include a mono- or di(halo)phenyl group suchas 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl, 2,4-difluorophenyl and the like; a mono- ordi(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl,2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and thelike; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenylgroup, for example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group suchas 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl,4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such 4-carboxyphenyl, a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methyl sulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, 2-chloro-5-difluoromethoxy and the like, aswell as trisubstituted phenyl groups where the substituents aredifferent, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino.

“Cycloalkyl” refers to a non-aromatic, saturated or partiallyunsaturated hydrocarbon ring group wherein the cycloalkyl group may beoptionally substituted independently with one or more substituentsdescribed herein. In one example, the cycloalkyl group is 3 to 12 carbonatoms (C₃-C₁₂). In other examples, cycloalkyl is C₃-C₈, C₃-C₁₀ orC₅-C₁₀. In other examples, the cycloalkyl group, as a monocycle, isC₃-C₈, C₃-C₆ or C₅-C₆. In another example, the cycloalkyl group, as abicycle, is C₇-C₁₂. In another example, the cycloalkyl group, as a spirosystem, is C₅-C₁₂. Examples of monocyclic cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements ofbicyclic cycloalkyls having 7 to 12 ring atoms include, but are notlimited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplarybridged bicyclic cycloalkyls include, but are not limited to,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.Examples of spiro cycloalkyl include, spiro[2.2]pentane,spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane andspiro[4.5]decane. In some embodiments, substituents for “optionallysubstituted cycloalkyls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonyl amino,methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, andpyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereofmay be optionally substituted, such as by one to four instances ofsubstituents selected from this same list.

“Guanidine” or “guanidinyl” means the group —NH—C(NH)—NHR in which R ishydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl,cycloalkyl, aryl and heterocyclyl groups are as defined herein. Aparticular guanidine is the group —NH—C(NH)—NH₂.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” are used interchangeably and refer to any mono-, bi-,tricyclic or spiro, saturated or unsaturated, aromatic (heteroaryl) ornon-aromatic (e.g., heterocycloalkyl), ring system, having 3 to 20 ringatoms, where the ring atoms are carbon, and at least one atom in thering or ring system is a heteroatom selected from nitrogen, sulfur oroxygen.

If any ring atom of a cyclic system is a heteroatom, that system is aheterocycle, regardless of the point of attachment of the cyclic systemto the rest of the molecule. In one example, heterocyclyl includes 3-11ring atoms (“members”) and includes monocycles, bicycles, tricycles andspiro ring systems, wherein the ring atoms are carbon, where at leastone atom in the ring or ring system is a heteroatom selected fromnitrogen, sulfur or oxygen. In one example, heterocyclyl includes 1 to 4heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms.In another example, heterocyclyl includes 3- to 7-membered monocycleshaving 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur oroxygen. In another example, heterocyclyl includes 4- to 6-memberedmonocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen,sulfur or oxygen. In another example, heterocyclyl includes 3-memberedmonocycles. In another example, heterocyclyl includes 4-memberedmonocycles. In another example, heterocyclyl includes 5-6 memberedmonocycles, e.g., 5-6 membered heteroaryl. In another example,heterocyclyl includes 3-11 membered heterocycloyalkyls, such as 4-11membered heterocycloalkyls. In some embodiments, a heterocycloalkylincludes at least one nitrogen. In one example, the heterocyclyl groupincludes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom mayoptionally be oxidized (e.g., NO, SO, SO₂), and any nitrogen heteroatommay optionally be quaternized (e.g., [Nlt₄]⁺Cl⁻, [NR₄]⁺OH⁻). Exampleheterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl,thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl,isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl,hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl,thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl,thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl,diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl,oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclescontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocycles containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles arebenzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example6-membered heterocycles contain one to three nitrogen atoms andoptionally a sulfur or oxygen atom, for example pyridyl, such aspyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yland pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are other example heterocycle groups.Heterocycles may be optionally substituted. For example, substituentsfor “optionally substituted heterocycles” include one to four instancesof F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃,COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl,cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl,difluoromethyl, sulfonyl amino, methanesulfonylamino, SO, SO₂, phenyl,piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl andheterocyclic portions thereof may be optionally substituted, such as byone to four instances of substituents selected from this same list.

“Heteroaryl” refers to any mono-, bi-, or tricyclic ring system where atleast one ring is a 5- or 6-membered aromatic ring containing from 1 to4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in anexample embodiment, at least one heteroatom is nitrogen. See, forexample, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^(th) ed.Table 7-2 [1985]. Included in the definition are any bicyclic groupswhere any of the above heteroaryl rings are fused to an aryl ring,wherein the aryl ring or the heteroaryl ring is joined to the remainderof the molecule. In one embodiment, heteroaryl includes 5-6 memberedmonocyclic aromatic groups where one or more ring atoms is nitrogen,sulfur or oxygen. Example heteroaryl groups include thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl,oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl andpurinyl, as well as benzo-fused derivatives, for example benzoxazolyl,benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl,benzoimidazolyl and indolyl. Heteroaryl groups can be optionallysubstituted. In some embodiments, substituents for “optionallysubstituted heteroaryls” include one to four instances of F, Cl, Br, I,OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy,ethoxy, propoxy, trifluoromethyl, difluoromethyl, sulfonylamino,methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, andpyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereofmay be optionally substituted, such as by one to four instances ofsubstituents selected from this same list.

“Heteroarylene” refers to a heteroaryl having two monovalent radicalcenters derived by the removal of two hydrogen atoms from two differentatoms of a parent heteroaryl group.

In particular embodiments, a heterocyclyl group is attached at a carbonatom of the heterocyclyl group. By way of example, carbon bondedheterocyclyl groups include bonding arrangements at position 2, 3, 4, 5,or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring,position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of apyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4,or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 ofan isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of anaziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3,4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way ofexample, nitrogen bonded heterocyclyl or heteroaryl groups includebonding arrangements at position 1 of an aziridine, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,position 2 of a isoindole, or isoindoline, position 4 of a morpholine,and position 9 of a carbazole, or β-carboline.

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, as defined herein.Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di-and tri-fluoromethoxy and cyclopropoxy.

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is hydrogen, alkyl, cycloalkyl, aryl orheterocyclyl, wherein the alkyl, cycloalkyl, aryl and heterocyclyl areas defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl(e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4,or 5 or more, or any range derivable therein) of the sub stituentslisted for that group in which said substituents may be the same ordifferent. In an embodiment, an optionally substituted group has 1substituent. In another embodiment an optionally substituted group has 2substituents. In another embodiment an optionally substituted group has3 substituents. In another embodiment an optionally substituted grouphas 4 substituents. In another embodiment an optionally substitutedgroup has 5 substituents.

Optional substituents for alkyl radicals, alone or as part of anothersubstituent (e.g., alkoxy), as well as alkylenyl, alkenyl, alkynyl,heteroalkyl, heterocycloalkyl, and cycloalkyl, also each alone or aspart of another substituent, can be a variety of groups, such as thosedescribed herein, as well as selected from the group consisting ofhalogen; oxo; CN; NO; N₃; —OR; perfluoro-C₁-C₄ alkoxy; unsubstitutedC₃-C₇ cycloalkyl; C₃-C₇ cycloalkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₆-C₁₀ aryl (e.g., phenyl); C₆-C₁₀ aryl substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S); 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S) substituted by halogen, OH, CN, unsubstituted C₁-C₆alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; —SR′; —SiR′R″R′″;—OC(O)R; —C(O)R; —CO₂R; —CONR′R″; —OC(O)NR′R″; —NR″C(O)R;—NR′″C(O)NR′R″; —NR″C(O)₂R; —S(O)₂R; —S(O)₂NR′R″; —NR′S(O)₂R″;—NR′″S(O)₂NR′R″; amidinyl; guanidinyl; —(CH₂)₁₋₄—OR; —(CH₂)₁₋₄—NR′R″;—(CH₂)₁₋₄—SR′; —(CH₂)₁₋₄—SiR′R″R′″; —(CH₂)₁₋₄—OC(O)R′; —(CH₂)₁₋₄—C(O)R′;—(CH₂)₁₋₄—CO₂R′; and —(CH₂)₁₋₄CONR′R″, or combinations thereof, in anumber ranging from zero to (2m′+1), where m′ is the total number ofcarbon atoms in such radical. R′, R″ and R′″ each independently refer togroups including, for example, hydrogen; unsubstituted C₁-C₆ alkyl;C₁-C₆ alkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆heteroalkyl; C₁-C₆ heteroalkyl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted by halogen, OH, CN,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, or NR′R″;unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS); and 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N and S)substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring wherein a ring atom is optionallysubstituted with N, O or S and wherein the ring is optionallysubstituted with halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″. For example, —NR′R″ is meantto include 1-pyrrolidinyl and 4-morpholinyl.

Similarly, optional substituents for the aryl and heteroaryl groups arevaried. In some embodiments, substituents for aryl and heteroaryl groupsare selected from the group consisting of halogen; CN; NO, N₃; —OR′;perfluoro-C₁-C₄ alkoxy; unsubstituted C₃-C₇ cycloalkyl; C₃-C₇ cycloalkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆-C₁₀ aryl (e.g., phenyl);C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S); 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; —NR′R″; —SR′; —SiR′R″R′″; —OC(O)R; —C(O)R′; —CO₂R;—CONR′R″; —OC(O)NR′R″; —NR″C(O)R′; —NR′″C(O)NR′R″; —NR″C(O)₂R′; —S(O)₂R;—S(O)₂NR′R″; —NR′S(O)₂R″; —NR′″S(O)₂NR′R″; amidinyl; guanidinyl;—(CH₂)₁₋₄—OR′; —(CH₂)₁₋₄—NR′R″; —(CH₂)₁₋₄—SR′; —(CH₂)₁₋₄—SiR′R″R′″;—(CH₂)₁₋₄—OC(O)R′; —(CH₂)₁₋₄—C(O)R′; —(CH₂)₁₋₄—CO₂R′; and—(CH₂)₁₋₄CONR′R″, or combinations thereof, in a number ranging from zeroto (2m′+1), where m′ is the total number of carbon atoms in suchradical. R′, R″ and R′″ each independently refer to groups including,for example, hydrogen; unsubstituted C₁-C₆ alkyl; C₁-C₆ alkylsubstituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆ heteroalkyl; C₁-C₆heteroalkyl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₆-C₁₀ aryl;C₆-C₁₀ aryl substituted by halogen, OH, CN, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S); and 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) substituted byhalogen, OH, CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″. When R′ and R″ are attached to the same nitrogen atom,they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring wherein a ring atom is optionally substituted with N, Oor S and wherein the ring is optionally substituted with halogen, OH,CN, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.For example, —NR′R″ is meant to include 1-pyrrolidinyl and4-morpholinyl.

The term “oxo” refers to ═O or (═O)₂.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicate the point ofattachment of the atom to which the wavy bond is connected in thechemical structure to the remainder of a molecule, or to the remainderof a fragment of a molecule. In some embodiments, an arrow together withan asterisk is used in the manner of a wavy line to indicate a point ofattachment.

In certain embodiments, divalent groups are described genericallywithout specific bonding configurations. It is understood that thegeneric description is meant to include both bonding configurations,unless specified otherwise. For example, in the group R¹-R²-R³, if thegroup R² is described as —CH₂C(O)—, then it is understood that thisgroup can be bonded both as R¹—CH₂C(O)—R³, and as R₁—C(O)CH₂—R³, unlessspecified otherwise.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that do not produce an adverse, allergic or otheruntoward reaction when administered to an animal, such as, for example,a human, as appropriate.

Compounds of the present invention may be in the form of a salt, such asa pharmaceutically acceptable salt. “Pharmaceutically acceptable salts”include both acid and base addition salts. “Pharmaceutically acceptableacid addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid and the like, and organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particular base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases include isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, a salt is selected from a hydrochloride,hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate,maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate,methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate,ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate,saccharinate, adipate, formate, glycolate, palmitate, L-lactate,D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate(e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate(ethane-1,2-di sulfonate or ethane-1-(sulfonic acid)-2-sulfonate),isethionate (2-hydroxyethyl sulfonate), 2-mesitylenesulphonate,2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate,L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate(2-mesitylenesulphonate), napsylate (2-naphthalenesulfonate), camsylate(camphor-10-sulphonate, for example (1 S)-(+)-10-camphorsulfonic acidsalt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate),orotate, xylate (p-xylene-2-sulphonate), and pamoic(2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-dicarboxylate).

A “sterile” formulation is aseptic or free from all livingmicroorganisms and their spores.

“Stereoisomers” refer to compounds that have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include diastereomers, enantiomers,conformers and the like.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties or biological activities. Mixturesof diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography such as HPLC.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. Many organic compounds exist in optically active forms,i.e., they have the ability to rotate the plane of plane-polarizedlight. In describing an optically active compound, the prefixes D and L,or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The prefixes d and 1 or (+) and (−)are employed to designate the sign of rotation of plane-polarized lightby the compound, with (−) or 1 meaning that the compound islevorotatory. A compound prefixed with (+) or d is dextrorotatory. For agiven chemical structure, these stereoisomers are identical except thatthey are mirror images of one another. A specific stereoisomer may alsobe referred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic mixture or a racemate, which may occur wherethere has been no stereoselection or stereospecificity in a chemicalreaction or process. The terms “racemic mixture” and “racemate” refer toan equimolar mixture of two enantiomeric species, devoid of opticalactivity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. A “solvate” refersto an association or complex of one or more solvent molecules and acompound of the present invention. Examples of solvents that formsolvates include water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine. Certain compounds of the presentinvention can exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are intended to be within the scope of thepresent invention. The term “hydrate” refers to the complex where thesolvent molecule is water.

A “metabolite” refers to a product produced through metabolism in thebody of a specified compound or salt thereof. Such products can result,for example, from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., 14C or ³H) isotope of a compound of the invention,administering it in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to ahuman, allowing sufficient time for metabolism to occur (typically about30 seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

“Amino-protecting group” as used herein refers to a derivative of thegroups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of such protecting groups include carbamates, amides, alkyl andaryl groups, and imines, as well as many N-heteroatom derivatives whichcan be removed to regenerate the desired amine group. Particular aminoprotecting groups are Pmb (p-Methoxybenzyl), Boc(tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz(Carbobenzyloxy). Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis,3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected amino”refers to an amino group substituted with one of the aboveamino-protecting groups.

“Carboxy-protecting group” as used herein refers to those groups thatare stable to the conditions of subsequent reaction(s) at otherpositions of the molecule, which may be removed at the appropriate pointwithout disrupting the remainder of the molecule, to give theunprotected carboxy-group. Examples of carboxy protecting groupsinclude, ester groups and heterocyclyl groups. Ester derivatives of thecarboxylic acid group may be employed to block or protect the carboxylicacid group while reactions are carried out on other functional groups onthe compound. Examples of such ester groups include substitutedarylalkyl, including substituted benzyls, such as 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4, 6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxybenzhydryl,2,2′,4,4′-tetramethoxybenzhydryl, alkyl or substituted alkyl esters suchas methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl),4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl,2-phenylprop-2-yl, thioesters such as t-butyl thioester, silyl esterssuch as trimethylsilyl, t-butyldimethylsilyl esters, phenacyl,2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl,beta-(di(n-butyl)methyl silyl)ethyl, p-toluene sulfonyl ethyl,4-nitrobenzylsulfonyl ethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. Another example of carboxy-protecting groups are heterocyclyl groups such as 1,3-oxazolinyl.Further examples of these groups are found in T. W. Greene and P. G. M.Wuts, “Protecting Groups in Organic Synthesis, 3^(rd) ed., John Wiley &Sons, Inc., 1999. The term “protected carboxy” refers to a carboxy groupsubstituted with one of the above carboxy-protecting groups.

“Hydroxy-protecting group” as used herein refers to a derivative of thehydroxy group commonly employed to block or protect the hydroxy groupwhile reactions are carried out on other functional groups on thecompound. Examples of such protecting groups includetetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g., TBS, TBDPS) groups. Further examples of these groups arefound in T. W. Greene and P. G. M. Wuts, “Protecting Groups in OrganicSynthesis, 3^(rd) ed., John Wiley & Sons, Inc., 1999. The term“protected hydroxy” refers to a hydroxy group substituted with one ofthe above hydroxy-protecting groups.

A “subject,” “individual,” or “patient” is a vertebrate. In certainembodiments, the vertebrate is a mammal. Mammals include, but are notlimited to, farm animals (such as cows), sport animals, pets (such asguinea pigs, cats, dogs, rabbits and horses), primates, mice and rats.In certain embodiments, a mammal is a human. In embodiments comprisingadministration of a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Igor II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, to a patient, the patient is typically in need thereof.

The term “Janus kinase” refers to JAK1, JAK2, JAK3 and TYK2 proteinkinases. In some embodiments, a Janus kinase may be further defined asone of JAK1, JAK2, JAK3 or TYK2. In any embodiment, any one of JAK1,JAK2, JAK3 and TYK2 may be specifically excluded as a Janus kinase. Insome embodiments, a Janus kinase is JAK1. In some embodiments, a Januskinase is a combination of JAK1 and JAK2.

The terms “inhibiting” and “reducing,” or any variation of these terms,includes any measurable decrease or complete inhibition to achieve adesired result. For example, there may be a decrease of about, at mostabout, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or anyrange derivable therein, reduction of activity (e.g., JAK1 activity)compared to normal.

In some embodiments, a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, is selective for inhibition of JAK1 over JAK3 and TYK2. In someembodiments, a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig orII, or a compound of any of Examples 1-1 to 1-249, 2-1 to 2-481 or 3-1,is selective for inhibition of JAK1 over JAK2, JAK3, or TYK2, or anycombination of JAK2, JAK3, or TYK2. In some embodiments, a compound ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any ofExamples 1-1 to 1-303, 2-1 to 2-486 or 3-1, is selective for inhibitionof JAK1 and JAK2 over JAK3 and TYK2. In some embodiments, a compound ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any ofExamples 1-1 to 1-303, 2-1 to 2-486 or 3-1, is selective for inhibitionof JAK1 over JAK3. By “selective for inhibition” it is meant that thecompound is at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any rangederivable therein, better inhibitor of a particular Janus kinase (e.g.,JAK1) activity compared to another particular Janus kinase (e.g., JAK1)activity, or is at least a 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or500-fold better inhibitor of a particular Janus kinase (e.g., JAK1)activity compared to another particular Janus kinase (e.g., JAK1)activity.

“Therapeutically effective amount” means an amount of a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id,Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to2-486 or 3-1, that (i) treats or prevents the particular disease,condition or disorder, or (ii) attenuates, ameliorates or eliminates oneor more symptoms of the particular disease, condition, or disorder, andoptionally (iii) prevents or delays the onset of one or more symptoms ofthe particular disease, condition or disorder described herein. In someembodiments, the therapeutically effective amount is an amountsufficient to decrease or alleviate the symptoms of an autoimmune orinflammatory disease (e.g., asthma). In some embodiments, atherapeutically effective amount is an amount of a chemical entitydescribed herein sufficient to significantly decrease the activity ornumber of B-cells. In the case of cancer, the therapeutically effectiveamount of the drug may reduce the number of cancer cells; reduce thetumor size; inhibit (i.e., slow to some extent and preferably stop)cancer cell infiltration into peripheral organs; inhibit (i.e., slow tosome extent and preferably stop) tumor metastasis; inhibit, to someextent, tumor growth; or relieve to some extent one or more of thesymptoms associated with the cancer. To the extent the drug may preventgrowth or kill existing cancer cells, it may be cytostatic or cytotoxic.For cancer therapy, efficacy can, for example, be measured by assessingthe time to disease progression (TTP) or determining the response rate(RR).

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include preventing occurrence or recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, decreasing the rate of disease progression,amelioration or palliation of the disease state, prolonging survival ascompared to expected survival if not receiving treatment and remissionor improved prognosis. In some embodiments, compounds of the invention,such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, ora compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, areused to delay development of a disease or disorder or to slow theprogression of a disease or disorder. Those in need of treatment includethose already with the condition or disorder as well as those prone tohave the condition or disorder, (for example, through a geneticmutation) or those in which the condition or disorder is to beprevented.

“Inflammatory disorder” refers to any disease, disorder or syndrome inwhich an excessive or unregulated inflammatory response leads toexcessive inflammatory symptoms, host tissue damage, or loss of tissuefunction. “Inflammatory disorder” also refers to a pathological statemediated by influx of leukocytes or neutrophil chemotaxis.

“Inflammation” refers to a localized, protective response elicited byinjury or destruction of tissues, which serves to destroy, dilute, orwall off (sequester) both the injurious agent and the injured tissue.Inflammation is notably associated with influx of leukocytes orneutrophil chemotaxis. Inflammation can result from infection withpathogenic organisms and viruses and from noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune responses. Accordingly,inflammatory disorders amenable to treatment with a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id,Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to2-486 or 3-1, encompass disorders associated with reactions of thespecific defense system as well as with reactions of the nonspecificdefense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity responses mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

The term “nonspecific defense system” refers to inflammatory disordersthat are mediated by leukocytes that are incapable of immunologicalmemory (e.g., granulocytes, and macrophages). Examples of inflammationthat result, at least in part, from a reaction of the nonspecificdefense system include inflammation associated with conditions such asadult (acute) respiratory distress syndrome (ARDS) or multiple organinjury syndromes; reperfusion injury; acute glomerulonephritis; reactivearthritis; dermatoses with acute inflammatory components; acute purulentmeningitis or other central nervous system inflammatory disorders suchas stroke; thermal injury; inflammatory bowel disease; granulocytetransfusion associated syndromes; and cytokine-induced toxicity.

“Autoimmune disease” refers to any group of disorders in which tissueinjury is associated with humoral or cell-mediated responses to thebody's own constituents. Non-limiting examples of autoimmune diseasesinclude rheumatoid arthritis, lupus and multiple sclerosis.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclearleukocytes such as neutrophils, basophils, and eosinophils), mast cells,dendritic cells, Langerhans cells, and endothelial cells). It will beappreciated by persons skilled in the art that the activation of one ora combination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory disorder.

In some embodiments, inflammatory disorders which can be treatedaccording to the methods of this invention include, but are not limitedto, asthma, rhinitis (e.g., allergic rhinitis), allergic airwaysyndrome, atopic dermatitis, bronchitis, rheumatoid arthritis,psoriasis, contact dermatitis, chronic obstructive pulmonary disease anddelayed hypersensitivity reactions.

The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and relatedterms refer to or describe the physiological condition in mammals thatis typically characterized by unregulated cell growth. A “tumor”comprises one or more cancerous cells. Examples of cancer includecarcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma,leukemia, and myeloid or lymphoid malignancies. More particular examplesof such cancers include squamous cell cancer (e.g., epithelial squamouscell cancer) and lung cancer including small-cell lung cancer, non-smallcell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamouscarcinoma of the lung. Other cancers include skin, keratoacanthoma,follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx(oral), lip, tongue, mouth, salivary gland, esophageal, larynx,hepatocellular, gastric, stomach, gastrointestinal, small intestine,large intestine, pancreatic, cervical, ovarian, liver, bladder,hepatoma, breast, colon, rectal, colorectal, genitourinary, biliarypassage, thyroid, papillary, hepatic, endometrial, uterine, salivarygland, kidney or renal, prostate, testis, vulval, peritoneum, anal,penile, bone, multiple myeloma, B-cell lymphoma, central nervous system,brain, head and neck, Hodgkin's, and associated metastases. Examples ofneoplastic disorders include myeloproliferative disorders, such aspolycythemia vera, essential thrombocytosis, myelofibrosis, such asprimary myelofibrosis, and chronic myelogenous leukemia (CML).

A “chemotherapeutic agent” is an agent useful in the treatment of agiven disorder, for example, cancer or inflammatory disorders. Examplesof chemotherapeutic agents are well-known in the art and includeexamples such as those disclosed in U.S. Publ. Appl. No. 2010/0048557,incorporated herein by reference. Additionally, chemotherapeutic agentsinclude pharmaceutically acceptable salts, acids or derivatives of anyof chemotherapeutic agents, as well as combinations of two or more ofthem.

“Package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products that contain informationabout the indications, usage, dosage, administration, contraindicationsor warnings concerning the use of such therapeutic products.

The terms “compound(s) of this invention,” and “compound(s) of thepresent invention” and the like, unless otherwise indicated, includecompounds of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or acompound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, andstereoisomers (including atropisomers), geometric isomers, tautomers,solvates, metabolites, isotopes, salts (e.g., pharmaceuticallyacceptable salts), and prodrugs thereof. In some embodiments, solvates,metabolites, isotopes or prodrugs are excluded, or any combinationthereof.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the present invention, such as a compound of Formula0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples1-1 to 1-249, 2-1 to 2-481 or 3-1, include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Isotopically-labeled compounds(e.g., those labeled with ³H and ¹⁴C) can be useful in compound orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, in compounds ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any ofExamples 1-1 to 1-303, 2-1 to 2-486 or 3-1, one or more hydrogen atomsare replaced by ²H or ³H, or one or more carbon atoms are replaced by¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds can generally be prepared by following procedures analogous tothose disclosed in the Schemes or in the Examples herein, bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent.

It is specifically contemplated that any limitation discussed withrespect to one embodiment of the invention may apply to any otherembodiment of the invention. Furthermore, any compound or composition ofthe invention may be used in any method of the invention, and any methodof the invention may be used to produce or to utilize any compound orcomposition of the invention.

The use of the term “or” is used to mean “and/or” unless explicitlyindicated to refer to alternatives only or the alternative are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

Inhibitors of Janus Kinases

One aspect of the invention provides compounds of Formula 0:

and stereoisomers and salts thereof, wherein:

Ar¹ is phenylene or 3-11 membered heteroarylene (e.g., 5-11, e.g., 5-6,membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS), wherein Ar¹ is optionally substituted;

X is —O— or —N(R^(1b))—(CR^(x1)R^(y1))_(p)—, wherein R^(x1) and R^(y1)are each independently hydrogen or C₁-C₆ alkyl and p is 0 to 6, andwherein the —N(R^(1b))— portion of —N(R^(1b))—(CR^(x1)R^(y1))_(p)— isbound to the carbonyl carbon of Formula 0;

R^(1a) is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, or 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) and R^(1a) isoptionally substituted by R⁹;

R^(1b) is hydrogen, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl, and wherein one ormore alkylene units of said alkyl group is optionally substituted by —O—and wherein any alkyl or cycloalkyl group is optionally substituted byOH, or

-   -   when p is 0 and X is —N(R^(1b))—, R^(1a) and R^(1b) may be        joined together with the nitrogen atom to which R^(1a) and        R^(1b) is attached to form a 3-11 membered heterocyclyl (e.g.,        5-6 membered heteroaryl containing 1 to 4 heteroatoms selected        from O, N and S or 4-11 membered heterocycloalkyl containing 1        to 4 heteroatoms selected from O, N and S) optionally        substituted by R⁹;

R² is a 3-11 membered heterocyclyl containing at least 1 nitrogen,selected from groups (a)-(e) and (h)-(j), or a C₅-C₈ cycloalkenyl ring(f), or a —O—(CR^(x)R^(y))_(q)—Ar² group (g) where R^(x) and R^(y) areindependently hydrogen or C₁-C₆ alkyl, q is 0 to 3 and Ar² is optionallysubstituted C₆-C₁₀ aryl or optionally substituted (e.g., by oxo or(C₁-C₆ alkyl)phenyl) 5-11 membered heteroaryl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or5-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S):

R³, R⁴ and R⁵ are each independently selected from the group consistingof hydrogen, CH₃, CH₂CH₃, OCH₃, CF₃, F and Cl;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, halogen, OH, CN, phenyl, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, (C₀-C₆ alkylene)3-11 membered heterocyclyl (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S), (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆alkylene)NR^(a)(O)(C₁-C₆ alkyl), (C₀-C₆ alkylene)NR^(a)(O)(phenyl),(C₀-C₆ alkylene)C(O)R^(8a), (C₀-C₆ alkylene)C(O)OR^(8a), C₁-C₆ alkoxy,—O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆ alkylene)C(O)NR^(a)R^(b), —C═N—O—(C₁-C₆alkyl), —O—(C₁-C₆ alkyl)3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S), (C₀-C₆ alkylene)NR^(a)SO₂(C₁-C₆ alkyl), (C₀-C₆alkylene)NR^(a)SO₂(phenyl), and —O-(3-11 membered heterocyclyl) (e.g.,5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from O, Nand S or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S); wherein said alkyl, alkylene, alkoxy,cycloalkyl, phenyl and heterocyclyl are each independently optionallysubstituted (e.g., by halogen, CN, oxo, OH, C₁-C₆ alkyl, —O(C₁-C₆alkylene)-O—(C₁-C₆ alkylene), CONR^(a)R^(b), CHF₂, CH₂F, CF₃, —S—(C₁-C₆alkyl), C₁-C₆ alkoxy, or NR^(a)R^(b));

or R₆ and R₇ together form an optionally substituted (e.g., C₁-C₆ alkyl,CN or oxo) phenyl or optionally substituted (e.g., C₁-C₆ alkyl, CN oroxo) 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS);

R⁸ is H, C₁-C₆ alkyl, (C₀-C₆ alkylene)phenyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, (C₀-C₆ alkylene)3-11 membered heterocyclyl (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S), C(O)NR^(a)R^(b), SO₂NR^(a)R^(b), (C₁-C₆alkylene)C(O)OR^(8a) or C(O)R^(8a), wherein said alkyl, alkylene,heterocyclyl and phenyl are each independently optionally substituted(e.g., C₁-C₆ alkyl, C₁-C₆ alkoxy or CN);

R^(8a) is H, NR^(a)R^(b), C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl,(C₀-C₆ alkylene)phenyl, or (C₀-C₆ alkylene)3-11 membered heterocyclyl(e.g., 5-6 membered heteroaryl containing 1 to 4 heteroatoms selectedfrom O, N and S or 4-11 membered heterocycloalkyl containing 1 to 4heteroatoms selected from O, N and S), wherein said alkyl, alkylene,cycloalkyl, phenyl and heterocyclyl are each independently optionallysubstituted (e.g., by halogen, OH, CN, NR^(a)R^(b), C₁-C₆ alkyl, C₁-C₆alkoxy, or oxo);

R^(8aa) is H, C₁-C₆ alkyl optionally substituted by OH, orC(O)NR^(a)R^(b); or

or R⁸ and R^(8aa) together form an optionally substituted (e.g., by oxo)3-11 membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS);

R⁹, independently at each occurrence, is OH, halogen, C₁-C₆ alkyl,(C₀-C₆ alkylene)C₃-C₈ cycloalkyl, (C₀-C₆ alkylene)phenyl, (C₀-C₆alkylene)3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS), (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆ alkylene)NR^(a)R^(b), orC(O)(C₁-C₆ alkyl), wherein said alkyl, alkylene, cycloalkyl, phenyl andheterocyclyl are each independently optionally substituted (e.g., by OH,CN, halogen, NR^(a)R^(b), 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S), or C₁-C₆ alkyl optionally substituted by halogen);

R^(a) and R^(b), independently at each occurrence, are selected from thegroup consisting of hydrogen, C₁-C₆ alkyl optionally substituted byhalogen or CN, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, or (C₀-C₆alkylene)phenyl, and wherein one or more alkylene units of any alkylgroup is independently optionally substituted by —O—, or alternativelyR^(a) and R^(b) may be joined together with the nitrogen atom to whichthey are attached to form an optionally substituted (e.g., by CN orC₁-C₆ alkyl) 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS);

m¹, m², m³ and m⁴ are each independently 0, 1 or 2; and

n is 0 or 1.

In some embodiments, a compound of Formula 0 is further defined as acompound of Formula I:

and stereoisomers and salts thereof, wherein:

Ar¹ is phenylene or 3-11 membered heteroarylene (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S),wherein Ar¹ is optionally substituted;

X is —O— or —N(R^(1b))—(CR^(x1)R^(y1))_(p)—, wherein R^(x1) and R^(y1)are each independently hydrogen or C₁-C₆ alkyl and p is 0 to 6, andwherein the —N(R^(1b))— portion of —N(R^(1b))—(CR^(x1)R^(y1))_(p)— isbound to the carbonyl carbon of Formula I, as in:

R^(1a) is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, or 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) and R^(1a) isoptionally substituted by R⁹;

R^(1b) is hydrogen, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl, and wherein one ormore alkylene units of said alkyl group is optionally substituted by —O—and wherein any alkyl or cycloalkyl group is optionally substituted byOH, or

-   -   when p is 0 and X is —N(R^(1b))—, R^(1a) and R^(1b) may be        joined together with the nitrogen atom to which R^(1a) and        R^(1b) is attached to form a 3-11 membered heterocyclyl (e.g.,        5-6 membered heteroaryl containing 1 to 4 heteroatoms selected        from O, N and S; a 4-11 membered heterocycloalkyl containing 1        to 4 heteroatoms selected from O, N and S; or the 3-11 membered        heterocyclyl contains at least one nitrogen) optionally        substituted by R⁹;

R² is a 3-11 membered heterocyclyl (e.g., 5-6 membered heteroaryl or4-11 membered heterocycloalkyl) containing at least 1 nitrogen, selectedfrom groups (a)-(e), or a C₅-C₈ cycloalkenyl ring (f), or a—O—(CR^(x)R^(y))_(q)—Ar² group (g) where R^(x) and R^(y) areindependently hydrogen or C₁-C₆ alkyl, q is 0 to 3 and Ar² is optionallysubstituted C₆-C₁₀ aryl or optionally substituted 5-11 memberedheteroaryl (e.g., 5-6 membered heteroaryl containing 1 to 4 heteroatomsselected from O, N and S:

R³, R⁴ and R⁵ are each independently selected from the group consistingof hydrogen, CH₃, CH₂CH₃, OCH₃, CF₃, F and Cl; for example, R³-R⁵ mayeach be hydrogen;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, halogen, OH, CN, phenyl, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, (C₀-C₆ alkylene)3-11 membered heterocyclyl (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S), (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆alkylene)NR^(a)C(O)(C₁-C₆ alkyl), (C₀-C₆ alkylene)C(O)R^(8a), (C₀-C₆alkylene)C(O)OR^(8a), C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆alkylene)C(O)NR^(a)R^(b), and —O-(3-11 membered heterocyclyl) (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S); wherein said alkyl, alkylene, alkoxy,cycloalkyl, phenyl and heterocyclyl are each independently optionallysubstituted,

or R₆ and R₇ together form an optionally substituted phenyl oroptionally substituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S);

R⁸ is C₁-C₆ alkyl, (C₀-C₆ alkylene)phenyl, C(O)NR^(a)R^(b),SO₂NR^(a)R^(b), C(O)OR^(8a) or C(O)R^(8a), wherein said alkyl, alkyleneand phenyl are each independently optionally substituted;

R^(8a) is C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, (C₀-C₆alkylene)phenyl, or (C₀-C₆ alkylene)3-11 membered heterocyclyl (e.g.,5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from O, Nand S or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S), wherein said alkyl, alkylene, cycloalkyl,phenyl and heterocyclyl are each independently optionally substituted;

R^(8aa) is H; or

or R⁸ and R^(8aa) together form an optionally substituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S);

R⁹, independently at each occurrence, is OH, halogen, C₁-C₆ alkyl,(C₀-C₆ alkylene)C₃-C₈ cycloalkyl, (C₀-C₆ alkylene)phenyl, (C₀-C₆alkylene)3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS), (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆ alkylene)NR^(a)R^(b), orC(O)(C₁-C₆ alkyl), wherein said alkyl, alkylene, cycloalkyl, phenyl andheterocyclyl are each independently optionally substituted;

R^(a) and R^(b) are independently at each occurrence selected from thegroup consisting of hydrogen, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, or (C₀-C₆ alkylene)phenyl, and wherein one or more alkyleneunits of any alkyl group is independently optionally substituted by —O—,or alternatively R^(a) and R^(b) may be joined together with thenitrogen atom to which they are attached to form an optionallysubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS);

m¹, m², m³ and m⁴ are each independently 0, 1 or 2; and

n is 0 or 1.

In some embodiments, a compound of Formula 0 is further defined as acompound of Formula Ia:

wherein Ar¹, X, R^(1a), R³-R⁷, m¹, m² and n are as defined herein.

In some embodiments, in a compound of the present invention, such as acompound of Formula 0, I or Ia, m¹ is 1 and m² is 1, or m¹ is 2 and m²is 1.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib or If, R⁶ and R⁷ are attached to thering at the same carbon atom. In some embodiments of a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib or If, R⁶is C₁-C₆ alkyl or C₁-C₆-alkoxy, and R⁷ is optionally substituted phenyl,such as phenyl substituted by halogen, CN, C₁-C₆ alkyl or C₁-C₆ alkoxy.In some embodiments in a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib or If, R⁶ is C₁-C₆ alkyl, C₃-C₆cycloalkyl or optionally substituted phenyl, such as phenyl substitutedby halogen, CN, C₁-C₆ alkyl or C₁-C₆ alkoxy, and R⁷ is OH, (C₀-C₆alkylene)C(O)NR^(a)R^(b), (C₀-C₆ alkylene)CN or —O—(C₀-C₆ alkyl)CN. Insome embodiments in a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib or If, R⁶ is hydrogen and R⁷ isselected from (C₀-C₆ alkylene)C(O) NR^(a)R^(b), (C₀-C₆ alkylene)CN,C₁-C₆-alkoxy, —O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆ alkylene)C(O)NR^(a)R^(b),and —O—(C₁-C₆ alkylene)CN. In some embodiments in a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib or If, R⁶and R⁷ together form a 3-11 membered heterocycloalkyl (such as aheterocycloalkyl containing at least one nitrogen) optionallysubstituted by oxo.

In some embodiments of compounds of the present invention, such as acompound of Formula 0, I or Ia, the moiety shown below,

is selected from

wherein R^(7a) is selected from hydrogen, halogen, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl and CN.

In some embodiments, a compound of Formula 0 is further defined as acompound of Formula Ib:

wherein Ar¹, X, R^(1a), R³-R⁷, m¹, m² and n are as defined herein.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I or Ib, m¹ is 1 and m² is 2, or m¹ is 2 and m²is 1, or m¹ is 1 and m² is 1.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib or If, R⁶ is H and R⁷ and issubstituted phenyl.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I or Ib, the moiety shown below,

is selected from

wherein R^(7a) is selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl and CN.

In some embodiments, a compound of Formula 0 is further defined as acompound of Formula Ic:

wherein Ar¹, X, R^(1a), R³-R⁵, R⁸, m³, m⁴ and n are as defined herein.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I or Ic, m³ is 1 and m⁴ is 1, or m³ is 1 and m⁴is 2, or m³ is 1 and m⁴ is 0.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ic, Id or Ie, the following moiety, shownbelow,

is selected from

In some embodiments, a compound of Formula 0 is further defined as acompound of Formula Id:

wherein Ar¹, R^(1a), R^(1b), R³-R⁵, R⁸, m³, m⁴ and n are as definedherein.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I or Id, m³ is 1 and m⁴ is 1, m³ is 1 and m⁴ is1, or m³ is 1 and m⁴ is 2.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ic, Id, or Ie, R⁸ is substituted phenyl, suchas mono- or disubstituted phenyl, C(O)NR^(a)R^(b) or C(O)R^(8a).

In some embodiments, a compound of Formula 0 is further defined as acompound of Formula Ie:

wherein Ar¹, R^(1a), R^(1b), R³-R⁶, R⁸, m³, m⁴ and n are as definedherein.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I or Ie, m³ is 0 and m⁴ is 1 or m³ is 1 and m⁴ is1.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ie or If, R⁶ is hydrogen.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Id, Ie or If, R⁸ is C(O)NR^(a)R^(b).

In some embodiments, a compound of Formula 0, is further defined as acompound of Formula If:

wherein Ar¹, R^(1a), R^(1b), R³-R⁷, m³, m⁴ and n are as defined herein.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I or If, m³ is 1 and m⁴ is 1.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or If, R⁷ is OH or C₁-C₆-alkoxy.

In some embodiments of compounds of the present invention, such as acompound of Formula 0, I, Ia, Ib, or If, one or both of R⁶ and R⁷ islocated at the para position of the ring. In some embodiments ofcompounds of the present invention, such as a compound of Formula 0, I,Ia, Ib, or If, R⁶ and R⁷ are attached to different ring atoms. In someembodiments of compounds of the present invention, such as a compound ofFormula 0, I, Ia, Ib, or If, R⁶ and R⁷ are both attached to the samering atom.

In some embodiments, a compound of Formula 0 is further defined as acompound of Formula Ig:

wherein Ar¹, R^(1a), R^(1b), R³-R⁵, R^(7a) and n are as defined herein,R^(7a) is selected from hydrogen, OH, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl and CN, and q is either 0 or 1, and when q is 1,then R^(x) and R^(y) are hydrogen.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, Ar¹ isunsubstituted phenylene or unsubstituted 3-11 membered heteroarylene. Insome embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, Ar¹ isoptionally substituted phenylene or optionally substituted pyrazolylene.In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, Ar¹ isunsubstituted phenylene or unsubstituted pyrazolylene. In someembodiments of a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, Ar¹ is unsubstitutedphenylene and n is 0. In some embodiments of a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,or Ig, Ar¹ is unsubstituted pyrazolylene and n is 1. In some embodimentsof a compound of the present invention, such as a compound of Formula 0,I, Ia, Ib, Ic, Id, Ie, If, or Ig, Ar¹, such as phenyl, is notsubstituted by halogen, methyl, methoxy, ethoxy, isopropoxy, OH, CF₃, or—OCH₂C(O)N(CH₃)₂. In some embodiments, Ar¹ is not unsubstituted orsubstituted pyridyl.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib or Ic, the moiety

is further defined as

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or Ic, —X—R^(1a) is C₁-C₆ alkoxy or—O-3-11 membered heterocycloalkyl (such as heterocycloalkyl containingat least one nitrogen). For example, —X—R^(1a) may be —OCH₃, —OC₂H₅, or

wherein R^(8a) is C₁-C₆ alkyl.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or Ic, —X—R^(1a) is—N(R^(1b))—(CR^(x1)R^(y1))_(p)—R^(1a). In some embodiments of a compoundof the present invention, such as a compound of Formula 0, I, Ia, Ib, orIc, R^(1b) is C₁-C₆ alkyl optionally substituted by C₁-C₆ alkoxy, p is0-3, R^(x1) and R^(y1) are each independently hydrogen or C₁-C₆ alkyl,R^(1a) is C₁-C₆ alkyl and R⁹ is NR^(a)R^(b). In other embodiments of acompound of the present invention, such as a compound of Formula 0, I,Ia, Ib, or Ic, R^(1b) is C₁-C₆ alkyl optionally substituted by C₁-C₆alkoxy, p is 0-3, R^(x1) and R^(y1) are each independently hydrogen orC₁-C₆ alkyl, and R^(1a) is 3-11 membered heterocyclyl (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S) optionally substituted by R⁹. In yet otherembodiments of a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, or Ic, p is 0 and R^(1a) and R^(1b) are joinedto form a 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N and S)optionally substituted by Win some embodiments of a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, or Ic,—X—R^(1a) is —N(R^(1b))—(CR^(x1)R^(y1))_(p)—R_(1a) and is selected from

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or Ic, —X—R^(1a) is—N(R^(1b))—(CR^(x1)R^(y1))_(p)—R^(1a) and is selected from

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R⁹ isoptionally substituted C₁-C₆ alkyl or optionally substituted 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S). For example, insome embodiments of compounds of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, or Ig, the optionalsubstituents of optionally substituted C₁-C₆ alkyl of R⁹ or optionallysubstituted 3-11 membered heterocyclyl of R⁹ are selected from OH; CN;NR^(a)R^(b); C₁-C₆ alkyl; C₃-C₈ cycloalkyl; C₁-C₆ alkoxy; phenyl; 3-11membered heterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S) optionallysubstituted by C₁-C₆ alkyl or NR^(a)R^(b); C(O)C₁-C₆ alkyl; andC(O)-3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N and S)optionally substituted by C₁-C₆ alkyl.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, the group—X—R^(1a) is a group selected from:

(i) A group

wherein R^(1b) and R^(1c) are independently hydrogen, C₁-C₆ alkyl orC₃-C₆ cycloalkyl and p1 and p2 are independently 0, 1 or 2;

(ii) A group

wherein R^(1b) is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; p is 0-6,such as 1-3; R^(x) and R^(y) are independently hydrogen or C₁-C₆ alkyl;Het¹ is a 5-, 6- or 7-membered heterocycloalkyl ring or a 6-memberedheteroaryl ring. Exemplary structures include

(iii) A group

wherein R^(1d) and R^(1c) are independently hydrogen, C₁-C₆ alkyl orC₃-C₆ cycloalkyl, or R^(1d) and R^(1c) are joined in a ring optionallycontaining a further heteroatom selected from O, N and S, such as onefurther N or one further O, and p1, p2 and p3 are independently 0, 1 or2. An exemplary group is

(iv) A group

wherein p1 and p2 are independently 0, 1 or 2; Het² is a 3-11 (e.g.,4-7) membered heterocycloalkyl ring or 3-11 (e.g., 5-6) memberedheteroaryl ring. Exemplary structures include

(v) A group

wherein p1 and p2 are independently 0, 1 or 2; Het² is a 3-11 (e.g.,4-7) membered heterocycloalkyl or 3-11 (e.g., 5-6) membered heteroarylring;

(vi) A bridged bicyclic group such as

and R^(1c) is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; or

wherein p is 0, 1 or 2, R^(1d) and R^(1e) are independently hydrogen,C₁-C₆ alkyl or C₃-C₆ cycloalkyl, or R^(1d) and R^(1e) are joined in aring optionally containing a further heteroatom selected from O, N andS, such as one further N or one further O;

(vii) A bridged bicyclic group such as

wherein R^(1b) is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

(viii) A spirocyclic group comprising two 4-, 5- or 6-membered ringsoptionally containing further 1-4 heteroatoms, selected from O, N and S,such as N or O, such as

wherein p1, p2, p3, p4 and p5 are independently selected from 0, 1 and2, R^(1b) is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, and R^(1c) ishydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl. An exemplary group is

(ix) A group

wherein R^(1b), R^(1c) and R^(1d) are independently hydrogen, C₁-C₆alkyl or C₃-C₆ cycloalkyl; p is 0-6, such as 1-3; R^(x) and R^(y) areindependently hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; or

(x) A bicyclic group

wherein p1, p2, p3 and p4 are independently selected from 0, 1 and 2 andR^(1c) is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl. An exemplary groupis

(xi) A bicyclic group

wherein p1 and p2 are independently 0, 1 or 2 and one of X¹ and X² isnitrogen and the other is CH;

(xii) A bicyclic group

wherein p1, p2, p3 and p4 are independently selected from 0, 1 and 2 andR^(1d) and R^(ie) are independently hydrogen, C₁-C₆ alkyl or C₃-C₆cycloalkyl or R^(1d) and R^(1e) are joined in a ring optionallycontaining a further 1-3 heteroatoms, such as O, N or S, such as afurther N atom or a further O atom;

(xiii) A bicyclic group

wherein p3 and p4 are independently 0, 1 or 2 and R^(1c) is hydrogen,C₁-C₆ alkyl or C₃-C₆ cycloalkyl; or

(xiv) A bicyclic group

wherein p4 is 0 or 1.

In some embodiments the group —X—R^(1a) is a group selected from:

(i) A group

wherein R^(1c) is hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl and p1 andp2 are independently 0, 1 or 2. An exemplary group is

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R^(1a) isselected from the following:

and stereoisomers thereof.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R^(1a) isselected from the moieities shown in Table I or Table II, orstereoisomers thereof. In some embodiments of a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,or Ig, R^(1a) is not hydrogen.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R² is selectedfrom the following:

and stereoisomers thereof.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R^(1b) ishydrogen or CH₃.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, p is 0, 1, 2 or3. In some embodiments of a compound of Formula 0, I, Ia, Ib, Ic, Id,Ie, If, or Ig, p is 0, 1 or 2.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R³, R⁴ and R⁵are each independently selected from the group consisting of hydrogen,CH₃, CH₂CH₃, OCH₃, CF₃, F and Cl. In some embodiments of a compound ofthe present invention, such as a compound of Formula 0, I, Ia, Ib, Ic,Id, Ie, If, or Ig, R³, R⁴ and R⁵ are each independently selected fromthe group consisting of hydrogen, CH₃, CH₂CH₃, CF₃, F and Cl. In someembodiments of a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R³ is hydrogen. In someembodiments of a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R⁴ is hydrogen. In someembodiments of a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R⁵ is hydrogen. In someembodiments of a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, R³, R⁴ and R⁵ are eachindependently hydrogen. In some embodiments of a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,or Ig, none of R³, R⁴ and R⁵ are OCH₃.

In some embodiments of a compound of the present invention such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, X is not O.

Another aspect of the invention provides compounds of Formula II:

and stereoisomers and salts thereof, wherein:

Q¹ is a 3-11 membered heterocyclyl (e.g., 5-6 membered heteroaryl or4-11 membered heterocycloalkyl) containing at least 1 nitrogen, selectedfrom groups (a)-(e), or a C₅-C₈ cycloalkenyl ring (f), or a—O—(CR^(x)R^(y))_(q)—Ar² group (g) where R^(x) and R^(y) areindependently hydrogen or C₁-C₆ alkyl, q is 0 to 3 and Ar² is optionallysubstituted C₆-C₁₀ aryl or optionally substituted 5-11 memberedheteroaryl:

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, halogen, OH, CN, phenyl, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, (C₀-C₆ alkylene)3-11 membered heterocyclyl (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S), (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆alkylene)NR^(a)C(O)(C₁-C₆ alkyl), (C₀-C₆ alkylene)C(O)R^(8a), (C₀-C₆alkylene)C(O)OR^(8a), C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆alkylene)C(O)NR^(a)R^(b), and —O-(3-11 membered heterocyclyl) (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S); wherein said alkyl, alkylene, alkoxy,cycloalkyl, phenyl and heterocyclyl are each independently optionallysubstituted,

or R₆ and R₇ together form an optionally substituted phenyl oroptionally substituted 3-11 membered heterocyclyl (e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S);

R⁸ is C₁-C₆ alkyl, (C₀-C₆ alkylene)phenyl, C(O)NR^(a)R^(b),SO₂NR^(a)R^(b), C(O)OR^(8a) or C(O)R^(8a), wherein said alkyl, alkyleneand phenyl are each independently optionally substituted;

R^(8a) is C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, (C₀-C₆alkylene)phenyl, or (C₀-C₆ alkylene)3-11 membered heterocyclyl (e.g.,5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from O, Nand S or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S), wherein said alkyl, alkylene, cycloalkyl,phenyl and heterocyclyl are each independently optionally substituted;

R^(8aa) is H; or

or R⁸ and R^(8aa) together form an optionally substituted 3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S);

R⁹, independently at each occurrence, is OH, halogen, C₁-C₆ alkyl,(C₀-C₆ alkylene)C₃-C₈ cycloalkyl, (C₀-C₆ alkylene)phenyl, (C₀-C₆alkylene)3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS), (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆ alkylene)NR^(a)R^(b), orC(O)(C₁-C₆ alkyl), wherein said alkyl, cycloalkyl, phenyl andheterocyclyl are each independently optionally substituted;

-   -   R^(a) and R^(b) are independently at each occurrence hydrogen,        C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, or (C₀-C₆        alkylene)phenyl, and wherein one or more alkylene units of any        alkyl group is independently optionally substituted by —O—, or        alternatively R^(a) and R^(b) may be joined together with the        nitrogen atom to which they are attached to form an optionally        substituted 3-11 membered heterocyclyl (e.g., 5-6 membered        heteroaryl containing 1 to 4 heteroatoms selected from O, N and        S or 4-11 membered heterocycloalkyl containing 1 to 4        heteroatoms selected from O, N and S);

m¹, m², m³ and m⁴ are each independently 0, 1 or 2; and

Q² is C₃-C₈ cycloalkyl optionally substituted with C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ heteroalkyl, F, Cl, Br, I, OH, SH, NH₂, CN or N₃.

In certain embodiments, Q¹ is ring (a). In certain embodiments, Q¹ isring (b). In certain embodiments, Q¹ is ring (c). In certainembodiments, Q¹ is ring (d). In certain embodiments, Q¹ is ring (e). Incertain embodiments, Q¹ is ring (f). In certain embodiments, Q¹ is ring(g). In certain embodiments, Q¹ is a C₃-C₈ cyclopropyl ring optionallysubstituted with one or more substituents selected from C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, F, Cl, Br, I, OH, CN, OCF₃ and N₃.In certain embodiments, Q² is a cyclopropyl group. In certainembodiments, Q² is a cyclobutanyl group. In certain embodiments, Q² is acyclopentyl group. In certain embodiments, Q² is a cyclohexyl group. Incertain embodiments, Q² is a cycloheptyl group. In certain embodiments,Q² is a cyclooctyl group. In certain embodiments, Q¹ is ring (a) and Q²is an unsubstituted C₃-C₈ cycloalkyl group. In certain embodiments, Q¹is ring (a) and Q² is an unsubstituted cyclopropyl group.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or If, R⁶ and R⁷ are attached to thering at the same carbon atom. In some embodiments of a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, or If, R⁶and R⁷ are independently selected from the group consisting of hydrogen;halogen; OH; CN; phenyl; phenyl substituted by halogen, CN, C₁-C₆ alkylor C₁-C₆ alkoxy; C₁-C₆ alkyl; C₁-C₆ alkyl substituted by OH or CN;(C₀-C₆ alkylene)C₃-C₈ cycloalkyl; (C₀-C₆ alkylene)3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S), such aspiperidinyl; (C₀-C₆ alkylene)C(O)NR^(a)R^(b); (C₀-C₆alkylene)NR^(a)C(O)(C₁-C₆ alkyl); (C₀-C₆ alkylene)C(O)R^(8a); (C₀-C₆alkylene)C(O)OR^(8a); C₁-C₆ alkoxy; C₁-C₆ alkoxy substituted by CN;—O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆ alkylene)C(O)NR^(a)R^(b), and —O-(3-11membered heterocyclyl) (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S).

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or If, R⁶ is C₁-C₆ alkyl orC₁-C₆-alkoxy, and R⁷ is optionally substituted phenyl, such as phenylsubstituted by halogen, CN, C₁-C₆ alkyl or C₁-C₆ alkoxy. In someembodiments in a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, or If, R⁶ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl oroptionally substituted phenyl, such as phenyl substituted by halogen,CN, C₁-C₆ alkyl or C₁-C₆ alkoxy, and R⁷ is OH, (C₀-C₆alkylene)C(O)NR^(a)R^(b), (C₀-C₆ alkylene)CN or —O—(C₀-C₆ alkyl)CN. Insome embodiments in a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or If, R⁶ is hydrogen and R⁷ isselected from (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆ alkylene)CN,C₁-C₆-alkoxy, —O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆ alkylene)C(O)NR^(a)R^(b),and —O—(C₁-C₆ alkylene)CN. In some embodiments in a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, or If, R⁶and R⁷ together form a 3-11 membered heterocycloalkyl, such ascontaining 1-4 heteroatoms selected from O, N and S, optionallysubstituted by oxo.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, or If, optional substituents of R⁶ andR⁷, or R⁶ taken together with R⁷, are selected from the group consistingof halogen, CN, OH, oxo, C₁-C₆ alkyl, C₁-C₆ alkoxy, and C₁-C₆alkoxy-C₁-C₆ alkyl-C₁-C₆ alkoxy.

In some embodiments of compounds of the present invention, such as acompound of Formula 0, I, Ic, Id, or Ie, R⁸ is selected from the R⁸examples of Table II. In some embodiments of compounds of the presentinvention, such as a compound of Formula 0, I, Ic, Id or Ie, R⁸ isselected from the group consisting of C₁-C₆ alkyl optionally substitutedwith halogen, CN, C₁-C₆ alkoxy, or OH; (C₀-C₆ alkylene)phenyl, such as(C₀-C₁ alkylene)phenyl, where the alkylene is unsubstituted, where thephenyl may be optionally substituted with halogen, CN, oxo or OH;C(O)NR^(a)R^(b), wherein R^(a) and R^(b) are each independently hydrogenor C₁-C₆ alkyl optionally substituted by halogen, OH or CN, or R^(a) andR^(b) together form a 3-11 membered heterocycloalkyl group, such ascontaining 1-4 heteroatoms selected from O, N and S, optionallysubstituted with C₁-C₆ alkyl, oxo, CN or OH; SO₂NR^(a)R^(b), whereinR^(a) and R^(b) are each independently hydrogen or C₁-C₆ alkyloptionally substituted by halogen, OH or CN, or R^(a) and R^(b) togetherform a 3-11 membered heterocycloalkyl group, such as containing 1-4heteroatoms selected from O, N and S, optionally substituted by C₁-C₆alkyl, halogen, oxo, CN or OH; C(O)OR^(8a) or C(O)R^(8a), wherein R^(8a)is C₁-C₆ alkyl optionally substituted by halogen, C₁-C₆ alkoxy, oxo, CNor OH, or R^(8a) is a C₃-C₈ cycloalkyl group optionally substituted byC₁-C₆ alkyl, or R^(8a) is a 3-11 membered heterocycloyalkyl, such ascontaining 1-4 heteroatoms selected from O, N and S, optionallysubstituted by C₁-C₆ alkyl, halogen, oxo, CN or OH.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ic, Id or Ie, optional substituents of R⁸ areselected from the group consisting of halogen, oxo, CN, OH, C₁-C₆ alkyl,NH₂, NH(C₁-C₆ alkyl), and N(C₁-C₆ alkyl)₂.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ic, Id or Ie, R⁸ and R^(8aa) together form a3-11 membered heterocyclyl (e.g., a 5-6 membered heteroaryl containing1-4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1-4 heteroatoms selected from O, N and S)optionally substituted by halogen, oxo, CN, OH, C₁-C₆ alkyl or C₁-C₆alkoxy.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, R⁶, R⁷ andR⁸ are each independently selected from C(O)NR^(a)R^(b), C(O)R^(8a), andC(O)OR^(8a). In some embodiments, R^(a)R^(b) are independently selectedfrom hydrogen, C₁-C₆ alkyl, or (C₁-C₆ alkylene)phenyl, or R^(a) andR^(b) are taken together to form a 3-11 membered heterocyclyl (e.g., a5-6 membered heteroaryl containing 1-4 heteroatoms selected from O, Nand S or 4-11 membered heterocycloalkyl containing 1-4 heteroatomsselected from O, N and S) optionally substituted by halogen, C₁-C₆alkyl, oxo, OH, CN, NH₂, NHCH₃, or N(CH₃)₂. In some embodiments, R^(8a)is selected from C₁-C₆ alkyl optionally substituted by halogen, CN, OH,NH₂, NHCH₃, or N(CH₃)₂; C₃-C₈ cycloalkyl optionally substituted by C₁-C₆alkyl or C₁-C₆ alkoxy; 3-11 membered heterocyclyl (e.g., a 5-6 memberedheteroaryl containing 1-4 heteroatoms selected from O, N and S or 4-11membered heterocycloalkyl containing 1-4 heteroatoms selected from O, Nand S) optionally substituted by halogen, CN, OH, oxo, NH₂, NHCH₃,N(CH₃)₂, or C₁-C₆ alkyl.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If or Ig, R⁹,independently at each occurrence, is OH; halogen; C₁-C₆ alkyl optionallysubstituted with halogen, OH, CN, C₁-C₆ alkoxy, 5-6 membered heteroaryl(e.g., containing 1-4 heteroatoms selected from O, N and S), 3-11membered heterocycloalkyl (e.g., containing 1-4 heteroatoms selectedfrom O, N and S), NH₂, NHCH₃, or N(CH₃)₂; NH₂, NHCH₃, or N(CH₃)₂; (C₀-C₆alkylene)C₃-C₈ cycloalkyl wherein the cycloalkyl is optionallysubstituted by halogen, C₁-C₆ alkyl, CN, OH, oxo or NR^(a)R^(b); (C₀-C₆alkylene)phenyl wherein the phenyl is optionally substituted by halogen,CN, OH, C₁-C₆ alkyl, or NR^(a)R^(b); (C₀-C₆ alkylene)3-11 memberedheterocyclyl (e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S), wherein theheterocyclyl is optionally substituted by halogen, CN, OH, oxo, C₁-C₆alkyl, C(O)C₁-C₆ alkyl, NR^(a)R^(b) or 5-6 membered heteroaryloptionally substituted by C₁-C₆ alkyl; (C₀-C₆ alkylene)C(O)NR^(a)R^(b);(C₀-C₆ alkylene)NR^(a)R^(b); or C(O)(C₁-C₆ alkyl); wherein unlessotherwise specified, R^(a) and R^(b) are independently at eachoccurrence hydrogen, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, or(C₀-C₆ alkylene)phenyl, and wherein one or more alkylene units of anyalkyl group is independently optionally substituted by —O—, oralternatively R^(a) and R^(b) may be joined together with the nitrogenatom to which they are attached to form an optionally substituted 3-11membered heterocyclyl, e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S, and wherein saidoptional substituents of said 3-11 membered heterocyclyl group areselected from CN, halogen, OH, C(O)CH₃, 5-6 membered heteroaryloptionally substituted by C₁-C₆ alkyl or halogen, and C₁-C₆ alkyloptionally substituted by halogen, OH, CN, oxo, or C₁-C₆ alkoxy. In someembodiments, R^(a) and R^(b) are selected from NH₂, NHCH₃, and N(CH₃)₂.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If or Ig, an optionalsubstituent of R⁹ is selected from the group consisting of halogen, CN,OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, or NR^(a)R^(b), wherein R^(a) and R^(b)are independently selected from the group consisting of NH₂, NHCH₃, andN(CH₃)₂, or R^(a) and R^(b) may be joined together with the nitrogenatom to which they are attached to form an optionally substituted 3-11membered heterocyclyl, e.g., 5-6 membered heteroaryl containing 1 to 4heteroatoms selected from O, N and S or 4-11 membered heterocycloalkylcontaining 1 to 4 heteroatoms selected from O, N and S, and wherein saidoptional substituents of said 3-11 membered heterocyclyl group areselected from CN, halogen, OH, C(O)(C₁-C₆ alkyl) (e.g., C(O)CH₃), 5-6membered heteroaryl optionally substituted with C₁-C₆ alkyl or halogen,and C₁-C₆ alkyl optionally substituted by halogen, OH, CN, oxo, OH orC₁-C₆ alkoxy.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, R^(a) andR^(b), independently at each occurrence, are selected from the groupconsisting of NH₂, NHCH₃, and N(CH₃)₂, or R^(a) and R^(b) may be joinedtogether with the nitrogen atom to which they are attached to form anoptionally substituted 3-11 membered heterocyclyl, e.g., 5-6 memberedheteroaryl containing 1 to 4 heteroatoms selected from O, N and S or4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms selectedfrom O, N and S, and wherein said optional substituents of said 3-11membered heterocyclyl group are selected from CN, halogen, OH,C(O)(C₁-C₆ alkyl) (e.g., C(O)CH₃), 5-6 membered heteroaryl containing 1to 4 heteroatoms selected from O, N and S optionally substituted withhalogen, OH, CN or C₁-C₆ alkyl, and C₁-C₆ alkyl optionally substitutedby halogen, OH, CN, oxo, OH or C₁-C₆ alkoxy.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, n is 0. In someembodiments of a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, n is 0 and p is 0. Insome embodiments of a compound of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, n is 0 and p is0-6. In some embodiments of a compound of the present invention, such asa compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, n is 0 and pis 1-6. In some embodiments, of a compound of the present invention,such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, or Ig, n is1 and p is 0. In some embodiments of a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,or Ig, n is 1 and p is 0-6. In some embodiments of a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id,Ie, If, or Ig, n is 1 and p is 1-6.

In some embodiments of a compound of the present invention, such as acompound of Formula 0, I or II, Ar² is unsubstituted phenyl. In someembodiments in a compound of the present invention, such as a compoundof Formula 0, I or II, Ar² is unsubstituted phenyl, q is 0 or 1, andR^(x) and R^(y) are each independently hydrogen.

In some embodiments, a compound of Formula 0 or I excludes a compound ofFormula Ia. In some embodiments, a compound of Formula 0 or I excludes acompound of Formula Ib. In some embodiments, a compound of Formula 0 orI excludes a compound of Formula Ic. In some embodiments, a compound ofFormula 0 or I excludes a compound of Formula Id. In some embodiments, acompound of Formula 0 or I excludes a compound of Formula Ie. In someembodiments, a compound of Formula 0 or I excludes a compound of FormulaIf. In some embodiments, a compound of Formula 0 or I excludes acompound of Formula Ig. In some embodiments, a compound of Formula 0 orI excludes two or more compounds of Formula Ia, Ib, Ic, Id, Ie, If orIg.

In any compound of the present invention, including a compound ofFormula 0 or I, Ia, Ib, Ic, Id, Ie, If, or Ig, any substituent indicatedas “optionally substituted”, such as portions of R², R⁶, R⁷, R⁶ togetherwith R⁷, R⁸, R^(8a), R⁸ together with R^(8aa), or R⁹, may be optionallysubstituted by, e.g., halogen; oxo; CN; NO; N₃; —OR; perfluoro-C₁-C₄alkoxy; unsubstituted C₃-C₇ cycloalkyl; C₃-C₇ cycloalkyl substituted byhalogen, CN, OH, unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy,oxo or NR′R″; unsubstituted C₆-C₁₀ aryl (e.g., phenyl); C₆-C₁₀ arylsubstituted by halogen, CN, OH, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, or NR′R″; unsubstituted 3-11 membered heterocyclyl (e.g.,5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from O, Nand S or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S); 3-11 membered heterocyclyl (e.g., 5-6membered heteroaryl containing 1 to 4 heteroatoms selected from O, N andS or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatomsselected from O, N and S) substituted by halogen, CN, OH, unsubstitutedC₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; —NR′R″; —SR′;—SiR′R″R′″; —OC(O)R′; —C(O)R′; —CO₂R; —CONR′R″; —OC(O)NR′R″; —NR″C(O)R′;—NR′″C(O)NR′R″; —NR″C(O)₂R; —S(O)₂R; —S(O)₂NR′R″; —NR′S(O)₂R″;—NR′″S(O)₂NR′R″; amidinyl; guanidinyl; —(CH₂)₁₋₄—OR; —(CH₂)₁₋₄—NR′R″;—(CH₂)₁₋₄—SR; —(CH₂)₁₋₄—SiR′R″R′″; —(CH₂)₁₋₄—OC(O)R′; —(CH₂)₁₋₄—C(O)R′;—(CH₂)₁₋₄—CO₂R′; and —(CH₂)₁₋₄CONR′R″, or combinations thereof, in anumber ranging from zero to (2m′+1), where m′ is the total number ofcarbon atoms in such radical. R′, R″ and R′″ each independently refer togroups including, for example, hydrogen; unsubstituted C₁-C₆ alkyl;C₁-C₆ alkyl substituted by halogen, CN, OH, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″; unsubstituted C₁-C₆heteroalkyl; C₁-C₆ heteroalkyl substituted by halogen, CN, OH,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, oxo or NR′R″;unsubstituted C₆-C₁₀ aryl; C₆-C₁₀ aryl substituted by halogen, CN, OH,unsubstituted C₁-C₆ alkyl, unsubstituted C₁-C₆ alkoxy, or NR′R″;unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N andS); and 3-11 membered heterocyclyl (e.g., 5-6 membered heteroarylcontaining 1 to 4 heteroatoms selected from O, N and S or 4-11 memberedheterocycloalkyl containing 1 to 4 heteroatoms selected from O, N and S)substituted by halogen, CN, OH, unsubstituted C₁-C₆ alkyl, unsubstitutedC₁-C₆ alkoxy, oxo or NR′R″. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring wherein a ring atom is optionallysubstituted with N, O or S and wherein the ring is optionallysubstituted with halogen, CN, OH, unsubstituted C₁-C₆ alkyl,unsubstituted C₁-C₆ alkoxy, oxo or NR′R″.

Also provided is a compound selected from Examples 1-1 to 1-303, 2-1 to2-486 and 3-1, or any combination thereof. See Table A. Althoughspecific salts may be shown in Table A, it is to be understood thatother salts are contemplated, as described herein. Should there be anydiscrepancy between an Example's structure in Table A and an Example ofTable I or II, Table A's structure prevails.

TABLE A Exemplary Compounds of the Present Invention Ex. Structure Name1-1

N-methyl-4[[8-(4- methyl-4-phenyl-1- piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-methyl-4-piperidyl) benzamide; hydrochloride1-2

4-[[8-(4-cyclohexyl-4- hydroxy-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-3

4-[[8-(4-hydroxy-1- piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide;hydrochloride 1-4

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(4-phenyl-3,6-dihydro-2H-pyridin-1- yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-5

4-[[8-(4-methoxy-4- phenyl-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1- methyl-4-piperidyl) benzamide;hydrochloride 1-6

4-[[8-(4-hydroxy-4- methyl-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1- methyl-4-piperidyl) benzamide;hydrochloride 1-7

4-[[8-(4-hydroxy-4- phenyl-azepan-1-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-8

4-[[8-(4-methoxy-1- piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4- piperidyl)benzamide 1-9

4-[[8-(4-acetamido-1- piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide;hydrochloride 1-10

4-[[8-(4- acetylpiperazin-1-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-11

4-[[8-(4-cyano-1- piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-12

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(1-piperidyl)-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide; dihydrochloride1-13

N-methyl-N-(1- methyl-4-piperidyl)-4-[[8- (4-phenylpiperazin-1-yl)-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 1-14

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(4-phenyl-2,3,6,7-tetrahydroazepin-1- yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-15

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(5-phenyl-2,3,4,7-tetrahydroazepin-1- yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-16

4-[[8-(4-fluoro-4- phenyl-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-17

4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-18

4-[[8-[4-(3- chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-19

4-[[8-[4-hydroxy-4-(3- pyridyl)-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-20

4-[[8-[4-hydroxy-4-(4- pyridyl)-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-21

4-[[8-[4-(4- cyanophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-22

4-[[8-[4-(3- cyanophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-23

4-[[8-[4- (cyanomethoxy)-1- piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-24

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(2-oxo-1-oxa-3,7-diazaspiro[4.4]nonan- 7-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-25

4-[[8-[(9aS)-3,4,6,7,9,9a- hexahydro-1H- pyrazino[2,1-c][1,4]oxazin-8-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-26

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(8-oxo-2,7-diazaspiro[4.4]nonan-2- yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-27

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(3-oxo-2,8-diazaspiro[4.5]decan- 8-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-28

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan- 8-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-29

4-[[8-[4-(1-hydroxy-1- methyl-ethyl)-1- piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-30

4-[[8-[4-(2-amino-2- oxo-ethyl)-4-phenyl-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-31

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(6-oxo-3,4,7,8,9,9a-hexahydro-1H- pyrazino[1,2- c]pyrimidin-2-yl)- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 1-32

4-[[8-[(9aS)-4-oxo- 6,7,8,9,9a-tetrahydro- 1H-pyrazino[2,1-c][1,4]oxazin-8-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-33

4-[[8-[(9aR)-4-oxo- 6,7,9,9a-tetrahydro- 1H-pyrazino[2,1-c][1,4]oxazin-8-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-34

4-[[8-[4-(3,3- dimethylazetidine-1- carbonyl)piperazin-1-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-35

4-[[8-[4-(2- chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-36

4-[[8-[4-(4-ethylphenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-37

4-[[8-[4-(4-fluorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-38

4-[[8-[4-hydroxy-4-(4- isopropylphenyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-39

4-[[8-[4-hydroxy-4-(p- tolyl)-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-40

4-[[8-[4-hydroxy-4-(4- methoxyphenyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-41

4-[[8-[4-(cyanomethyl)- 4-phenyl-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-42

4-[[8-[4-(3,3- dimethylazetidine-1- carbonyl)-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-43

4-[[8-(4-hydroxy-4- phenyl-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-44

4-[[8-[4-[[2-(2- methoxyethoxy)-4- pyridyl]methoxy]-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-45

4-[[8-(4-cyano-4- phenyl-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-46

4-[[8-(3,4-dihydro- 1H-isoquinolin-2-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-47

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- (methylamino)azetidin- 1-yl]methanone1-48

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2- methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-5-yl)methanone 1-49

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(7- methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan- 3-yl)methanone 1-50

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(9- methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan- 7-yl)methanone 1-51

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- hydroxy-4-(pyrrolidin-1-ylmethyl)azepan-1- yl]methanone 1-52

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (1-methyl-2- piperidyl)pyrrolidin-1-yl]methanone 1-53

1-[2-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]-2,6-diazaspiro[3.3]heptan- 6-yl]ethanone 1-54

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(4- cyclopropylpiperazin- 1-yl)methanone1-55

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(3- methyl-3,6- diazabicyclo[3.2.1]octan-6-yl)methanone 1-56

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(4- cyclobutylpiperazin-1- yl)methanone1-57

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(5-methyl-3- pyridyl)methyl]benzamide 1-58

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(6-methyl-3- pyridyl)methyl]benzamide 1-59

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(7- methyl-2,7- diazaspiro[3.4]octan-2-yl)methanone 1-60

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(5- methyl-2,5- diazaspiro[3.4]octan-2-yl)methanone 1-61

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(4-methyl-1- piperidyl)ethyl]benzamide 1-62

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-methylpyrrolidin-3- yl)benzamide 1-63

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(4-methyl-2- pyridyl)methyl]benzamide 1-64

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(2-methyl-3- pyridyl)methyl]benzamide 1-65

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(1-ethylpyrrolidin- 3-yl)methyl]-N-methyl-benzamide 1-66

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(8- methyl-2,8- diazaspiro[5.5]undecan-2-yl)methanone 1-67

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- [(1-methylimidazol-2-yl)methyl]piperazin-1- yl]methanone 1-68

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (3-pyridyl)pyrrolidin- 1-yl]methanone1-69

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[6- (hydroxymethyl)-4-methyl-1,4-diazepan- 1-yl]methanone 1-70

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl-(8- methyl-5-oxa-2,8- diazaspiro[3.5]nonan-2-yl)methanone 1-71

4-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]- N,N,1-trimethyl-piperazine-2- carboxamide 1-72

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (5-methyl-2- pyridyl)pyrrolidin-1-yl]methanone 1-73

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- [6-(dimethylamino)-2-methyl-pyrimidin-4- yl]-1-piperidyl]methanone 1-74

1-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]- N,N-dimethyl-2-(4-pyridyl)pyrrolidine-2- carboxamide 1-75

[(3aS,6aS)-1-methyl- 2,3,3a,4,6,6a- hexahydropyrrolo[3,4-b]pyrrol-5-yl]-[4-[[8- [4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] phenyl]methanone 1-76

[(3aS,6aS)-5-methyl- 2,3,3a,4,6,6a- hexahydropyrrolo[2,3-c]pyrrol-1-yl]-[4-[[8- [4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] phenyl]methanone 1-77

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl)-[4- [(dimethylamino)methyl]-4-hydroxy-azepan-1- yl]methanone 1-78

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- (4-methylpiperazine-1-carbonyl)morpholin- 4-yl]methanone 1-79

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- [4-(dimethylamino)-6- methyl-2-pyridyl]pyrrolidin-1- yl]methanone 1-80

[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[3-[2-(dimethylamino)ethyl]- 1-piperidyl]methanone 1-81

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(7- methyl-2,7- diazaspiro[3.5]nonan-2-yl)methanone 1-82

1-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]- N,N,4-trimethyl-piperazine-2- carboxamide 1-83

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (4-pyridyl)-1- piperidyl]methanone1-84

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4-(2- hydroxyethyl)piperazin-1-yl]methanone 1-85

4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-[2-(2- pyridyl)ethyl]benzamide 1-86

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (dimethylamino)-1- piperidyl]methanone1-87

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1- methylpyrrolidin-3- yl)benzamide1-88

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- (dimethylamino)pyrrolidin-1-yl]methanone 1-89

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(3R)-quinuclidin- 3-yl]benzamide 1-90

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(4- methylpiperazin-1- yl)methanone 1-91

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(2,6- dimethylmorpholin-4-yl)ethyl]benzamide 1-92

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-methylazetidin- 3-yl)benzamide 1-93

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1,1-dimethyl-2- morpholino- ethyl)benzamide1-94

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(2-methyl-2-morpholino- propyl)benzamide 1-95

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(4-hydroxy-1- piperidyl)ethyl]benzamide 1-96

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[3-(4- methylpiperazin-1- yl)propyl]benzamide1-97

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(4- methylpiperazin-1- yl)ethyl]benzamide1-98

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(3-morpholinopropyl) benzamide 1-99

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[1-methyl-2-(1- piperidyl)ethyl]benzamide 1-100

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(3-methyl-1- piperidyl)ethyl]benzamide 1-101

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(2-morpholinoethyl) benzamide 1-102

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(1- methylpyrrolidin-2- yl)ethyl]benzamide1-103

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(1-methyl-2-piperidyl) methyl]benzamide 1-104

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(1-methyl-4-piperidyl) methyl]benzamide 1-105

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-methyl-4- piperidyl)benzamide 1-106

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(2-pyrrolidin-1- ylethyl)benzamide 1-107

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(dimethylamino)- 1-methyl-ethyl]benzamide1-108

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(dimethylamino) ethyl]benzamide 1-109

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-[(3-methyl- 2-pyridyl)methyl]benzamide 1-110

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (3-pyridyl)-1- piperidyl]methanone1-111

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(4- pyridylmethyl)benzamide 1-112

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2-pyridyl)piperazin-1- yl]methanone1-113

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (4-methylpiperazine- 1-carbonyl)-1-piperidyl]methanone 1-114

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (4-pyridyl)-1,4-diazepan-1-yl]methanone 1-115

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-ethyl-N-(4- pyridylmethyl)benzamide 1-116

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2-imidazol-1- ylethyl)piperazin-1-yl]methanone 1-117

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (4-methylpiperazin-1-yl)-1-piperidyl]methanone 1-118

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2,6-dimethylmorpholin- 4-yl)-1-piperidyl]methanone 1-119

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2-morpholinoethyl)piperazin-1-yl]methanone 1-120

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(2-methoxyethyl)- N-(1-methyl-4-piperidyl)benzamide 1-121

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (2-pyridylmethyl)-1-piperidyl]methanone 1-222

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2-pyridylmethyl)piperazin-1-yl]methanone 1-123

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (3-pyridylmethyl)piperazin-1-yl]methanone 1-124

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (2-pyridylmethyl)pyrrolidin-1-yl]methanone 1-125

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(4- morpholino-1- piperidyl)methanone1-126

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (3-pyridyl)piperazin- 1-yl]methanone1-127

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(3- morpholinopyrrolidin- 1-yl)methanone1-128

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-cyclopropyl-N-(1- methyl-4- piperidyl)benzamide1-129

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]-N- [(1-isopropylpyrrolidin-3- yl)methyl]-N-methyl-benzamide 1-130

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-isopropyl-4- piperidyl)-N-methyl- benzamide1-131

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(4- isobutylpiperazin-1- yl)methanone1-132

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(4- pyrrolidin-1-yl-1- piperidyl)methanone1-133

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2-methoxyethyl)piperazin-1-yl]methanone 1-134

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-[2-(3- pyridyl)ethyl]benzamide 1-135

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-[2-(4- pyridyl)ethyl]benzamide 1-136

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (cyclopropylmethyl)piperazin-1-yl]methanone 1-137

1,3,4,6,7,8,9,9a- octahydropyrido[1,2- a]pyrazin-2-yl-[4-[[8-[4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-138

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(3- pyridylmethyl)benzamide 1-139

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- [2-(dimethylamino) ethyl]piperazin-1-yl]methanone 1-140

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[1-(6-methyl-2- pyridyl)ethyl]benzamide 1-141

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(1-methyl-3- piperidyl)methyl] benzamide 1-142

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-cyclopropyl-N-(2- pyridylmethyl)benzamide 1-143

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]traizolo[1,5-a]pyridin-2- yl]amino]phenyl]-(3- morpholino-1- piperidyl)methanone1-144

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2-pyridyl)-1- piperidyl]methanone1-145

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (3-pyridylmethyl)-1-piperidyl]methanone 1-146

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- (4-pyridylmethyl)pyrrolidin-1-yl]methanone 1-147

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (4-pyridyl)pyrrolidin- 1-yl]methanone1-148

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[2- (2-pyridyl)morpholin- 4-yl]methanone1-149

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- (2-pyridyl)-1- piperidyl]methanone1-150

4-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]-N- methyl-1-(2-phenylethyl)piperazine- 2-carboxamide 1-151

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- [[6-(dimethylamino) pyrimidin-4-yl]methyl]pyrrolidin- 1-yl]methanone 1-152

1-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]-N,4-dimethyl-piperazine- 2-carboxamide 1-153

1-benzyl-4-[4-[[8-[4- (4-chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]-N-methyl-piperazine-2- carboxamide 1-154

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(1-methyl-4- piperidyl)ethyl]benzamide 1-155

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3-(3- pyridylmethyl)pyrrolidin-1-yl]methanone 1-156

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- [(5-methyl-2-pyridyl)methyl]pyrrolidin-1- yl]methanone 1-157

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3-(2- pyridylmethyl)pyrrolidin-1-yl]methanone 1-158

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (2-pyridylmethyl)-1-piperidyl]methanone 1-159

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(6-methyl-2- pyridyl)ethyl]benzamide 1-160

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(3- pyridyl)ethyl]benzamide 1-161

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(4- pyridyl)ethyl]benzamide 1-162

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(2- pyridyl)ethyl]benzamide 1-163

4-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]-N,1-dimethyl-piperazine- 2-carboxamide 1-164

1-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]- N,N-dimethyl-azetidine-3-carboxamide 1-165

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- (4-methylpiperazine-1-carbonyl)azetidin-1- yl]methanone 1-166

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]- [(3S)-3-(dimethylamino)pyrrolidin-1-yl]methanone 1-167

3-[4-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] benzoyl]piperazin-1-yl]propanenitrile 1-168

3,4,6,7,8,8a-hexahydro- 1H-pyrrolo[1,2-a]pyrazin- 2-yl-[4-[[8-[4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-169

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(6- quinolylmethyl) benzamide 1-170

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-[(1-methyl- 3-piperidyl)methyl]benzamide 1-171

N-(1-benzylpyrrolidin- 3-yl)-4-[[8-[4-(4- chlorophenyl)-4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-benzamide 1-172

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[4- (tetrahydrofuran-2-ylmethyl)piperazin-1- yl]methanone 1-173

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(1- piperidyl)ethyl]benzamide 1-174

1-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzoyl]-4-isopropyl-N-methyl- piperazine-2-carboxamide 1-175

N-(2-aminoethyl)-4- [[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 1-176

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-pyrrolidin-3-yl- benzamide 1-177

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]- piperazin-1-yl-methanone 1-178

(1-methyl-4-piperidyl) 4-[[8-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoate 1-179

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(3-piperidyl)benzamide 1-180

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(pyrrolidin-3- ylmethyl)benzamide 1-181

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(4-piperidyl)benzamide 1-182

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(pyrrolidin-2- ylmethyl)benzamide 1-183

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(3-piperidylmethyl) benzamide 1-184

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(4-piperidylmethyl) benzamide 1-185

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(2-piperidylmethyl) benzamide 1-186

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[2-(3-piperidyl) ethyl]benzamide 1-187

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(2-piperazin-1- ylethyl)benzamide 1-188

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(morpholin-2- ylmethyl)benzamide 1-189

(3-aminoazetidin-1-yl)-[4- [[8-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]phenyl]methanone 1-190

3,3a,4,5,6,6a-hexahydro- 2H-pyrrolo[2,3-c]pyrrol- 1-yl-[4-[[8-[4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-191

[3-(aminomethyl)azetidin- 1-yl]-[4-[[8-[4-(4- chlorophenyl)-4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]phenyl]methanone 1-192

[3- (aminomethyl)pyrrolidin- 1-yl]-[4-[[8-[4-(4-chlorophenyl)-4-hydroxy- 1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-193

[4-(aminomethyl)-1- piperidyl]-[4-[[8-[4- (4-chlorophenyl)-4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]phenyl]methanone 1-194

N-(2-aminoethyl)-4- [[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-benzamide 1-195

[2- (aminomethyl)pyrrolidin- 1-yl]-[4-[[8-[4-(4- chlorophenyl)-4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]phenyl]methanone 1-196

[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[2-(hydroxymethyl)piperazin- 1-yl]methanone 1-197

2,3,3a,4,6,6a-hexahydro- 1H-pyrrolo[3,4-c]pyrrol- 5-yl-[4-[[8-[4-(4-chlorophenyl)-4-hydroxy- 1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-198

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-[(3S)-3- piperidyl]benzamide 1-199

[4- [[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-(2,7-diazaspiro[3.5]nonan-2- yl)methanone 1-200

[4- [[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-(3-methylpiperazin-1- yl)methanone 1-201

[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-(2,7-diazaspiro[3.5]nonan- 7-yl)methanone 1-202

4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(3- piperidyl)benzamide 1-203

[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-(2,6-diazaspiro[3.3]heptan- 2-yl)methanone 1-204

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]- (1,4-diazepan-1- yl)methanone 1-205

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,6- diazaspiro[3.4]octan-6- yl)methanone1-206

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-[3- (methylamino)pyrrolidin-1-yl]methanone 1-207

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,7- diazaspiro[4.4]nonan- 2-yl)methanone1-208

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,7- diazaspiro[4.4]nonan- 7-yl)methanone1-209

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,7- diazaspiro[4.4]nonan- 1-yl)methanone1-210

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,8- diazaspiro[3.5]nonan- 2-yl)methanone1-211

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,6- diazaspiro[4.5]decan- 2-yl)methanone1-212

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,9- diazaspiro[4.5]decan- 2-yl)methanone1-213

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,8- diazaspiro[4.5]decan- 8-yl)methanone1-214

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,8- diazaspiro[4.5]decan- 2-yl)methanone1-215

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,8- diazaspiro[5.5]undecan-2-yl)methanone 1-216

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,9- diazaspiro[5.5]undecan-2-yl)methanone 1-217

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,9- diazaspiro[5.5]undecan-9-yl)methanone 1-218

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(3,9- diazaspiro[5.5]undecan-3-yl)methanone 1-219

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,8- diazaspiro[5.5]undecan-8-yl)methanone 1-220

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-oxa-8- azaspiro[4.5]decan-3-ylmethyl)benzamide 1-221

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-oxa-8- azaspiro[4.5]decan-3- yl)benzamide1-222

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(1-oxa-8- azaspiro[4.5]decan-2-ylmethyl)benzamide 1-223

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,9- diazaspiro[4.6]undecan-9-yl)methanone 1-224

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(2,7- diazaspiro[3.4]octan-2- yl)methanone1-225

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1- oxa-4,8- diazaspiro[5.5]undecan-4-yl)methanone 1-226

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,8- diazaspiro[4.5]decan- 8-yl)methanone1-227

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,8- diazaspiro[4.5]decan- 1-yl)methanone1-228

(2-amino-7- azaspiro[3.5]nonan-7- yl)-[4-[[8-[4-(4- chlorophenyl)-4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]phenyl]methanone 1-229

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1- oxa-4,8- diazaspiro[5.5]undecan-8-yl)methanone 1-230

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1- oxa-4,9- diazaspiro[5.5]undecan-9-yl)methanone 1-231

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1- oxa-4,9- diazaspiro[5.5]undecan-4-yl)methanone 1-232

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]- [(1R,5R)-3,6- diazabicylo[3.2.0]heptan-3-yl]methanone 1-233

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,9- diazaspiro[4.5]decan- 1-yl)methanone1-234

[(3aS,6aS)-2,3,3a,4,6,6a- hexahydro-1H- pyrrolo[2,3-c]pyrrol-5-yl]-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] phenyl]methanone 1-235

[(3aR,6aS)-2,3,3a,4,6,6a- hexahydro-1H- pyrrolo[3,4-c]pyrrol-5-yl]-[4-[[8-[4-(4- chlorophenyl)-4-hydroxy- 1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] phenyl]methanone 1-236

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(1,7- diazaspiro[3.5]nonan- 7-yl)methanone1-237

[(1S,5R)-5-amino-3- azabicyclo[3.1.0]hexan- 3-yl]-[4-[[8-[4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-238

N-[(1R,5S)-3- azabicyclo[3.1.0]hexan- 6-yl]-4-[[8-[4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-239

[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]phenyl]-(9- oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)methanone 1-240

[4-(aminomethyl)-3- azabicyclo[2.1.1]hexan- 3-yl]-[4-[[8-[4-(4-chlorophenyl)-4- hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-241

[(3aS,6aS)-3,3a,4,5,6,6a- hexahydro-2H- pyrrolo[2,3-c]pyrrol-1-yl]-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] phenyl]methanone 1-242

[(4aR,7aR)-3,4a,5,6,7,7a- hexahydro-2H- pyrrolo[3,4-b][1,4]oxazin-4-yl]-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] phenyl]methanone 1-243

[(4aS,7aR)-3,4a,5,6,7,7a- hexahydro-2H- pyrrolo[3,4-b][1,4]oxazin-4-yl]-[4-[[8-[4-(4- chlorophenyl)-4- hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] phenyl]methanone 1-244

2,3,4a,5,6,7,8,8a- octahydropyrido[4,3- b][1,4]oxazin-4-yl-[4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino] phenyl]methanone 1-245

4-[[8-[4-(4-chlorophenyl)- 4-hydroxy-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-(2-oxa-9- azaspiro[5.5]undecan-3-ylmethyl)benzamide 1-246

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-247

4-[[8-[4-(4-chlorophenyl)- 4-(2-cyanoethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-248

N-methyl-N-(1- methyl-4-piperidyl)-4- [(8-phenoxy- [1,2,4]triazolo[1,5-a]pyridin-2- yl)amino]benzamide 1-249

4-[(8-benzyloxy- [1,2,4]triazolo[1,5- a]pyridin-2-yl)amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-250

4-[[8-[4-(4- chlorophenyl)-4-[(E)- methoxyiminomethyl]- 1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-251

4-[[8-[4- (hydroxymethyl)-4-(4- methylsulfanylphenyl)- 1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-252

4-[[8-[4-(4-chlorophenyl)- 4-(1-hydroxyethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-253

4-[[8-[4-(4-chlorophenyl)- 4-(2,2,2-trifluoro-1- hydroxy-ethyl)-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-254

ethyl 2-[4-(4- chlorophenyl)-1-[2-[4- [methyl-(1-methyl-4-piperidyl)carbamoyl] anilino-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-4-piperidyl]acetate 1-255

4-[[8-[4-(4-chlorophenyl)- 4-(2-hydroxyethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide; formic acid 1-256

4-[[8-[4-(4-chlorophenyl)- 4-(2,2,-difluoroethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide; formic acid 1-257

4-[[8-[4-(cyanomethyl)- 4-cyclopentyl-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-258

4-[[8-[4-(4-chlorophenyl)- 4-(methoxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide; formic acid 1-259

N-benzyl-4-methyl-1- [2-[4-[methyl-(1-methyl- 4-piperidyl)carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8- yl]piperidine-4- carboxamide1-260

4-[[8-(4-acetamido-4- methyl-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-261

4-[[8-[4- [benzenesulfonyl(methyl) amino]-4-methyl-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-262

4-[[8-[4-(4-chlorophenyl)- 4-methyl-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-263

4-[[8-[4-(4-chloro-3- fluoro-phenyl)-4- (cyanomethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-264

4-[[8-[(3-benzyl-2- oxo-1,3-benzoxazol-5- yl)oxy]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-265

4-[[8-[4-(aminomethyl)- 4-(4-chlorophenyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide; formic acid 1-266

4-[[8-[4-(hydroxymethyl)- 4-[(2,2,2- trifluoroethylamino)methyl]-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-267

4-[[8-[4-[4- difluoromethyl)phenyl]- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-268

4-[[8-[4- (acetamidomethyl)-4- (4-chlorophenyl)-1- piperidyl]-[1,2,4]triazolo[1,5- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-269

4-(4-chlorophenyl)-1- [2-[4-[methyl-(1- methyl-4-piperidyl)carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8- yl]piperidine-4-carboxylic acid; formic acid 1-270

4-[[8-[4-(4- chlorophenyl)-4-(1,2- dihydroxyethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-271

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-[[1-(2,2,2-trifluoroethyl)-4- piperidyl]methyl] benzamide 1-272

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-[2-(3-methyl-1-piperidyl)ethyl]benzamide 1-273

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-[2-(3,5-dimethyl-1-piperidyl)ethyl]benzamide 1-274

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-(5- methyl-2,5-diazaspiro[3.4]octan- 2-yl)methanone 1-275

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-(1-methyl-2,3,3a,4,6,6a- hexahydropyrrolo[2,3- c]pyrrol-5-yl)methanone1-276

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[4- (2-pyridyl)-1-piperidyl]methanone 1-277

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-[2-[(2S,6S)-2,6-dimethylmorpholin-4- yl]ethyl]benzamide 1-278

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-[2-[(2R,6S)-2,6-dimethylmorpholin-4- yl]ethyl]benzamide 1-279

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[3-(4-pyridyl)pyrrolidin- 1-yl]methanone 1-280

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-(1-cyclopentyl-4-piperidyl)benzamide 1-281

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[4- [(2S,6S)-2,6-dimethylmorpholin-4- yl]-1-piperidyl] methanone 1-282

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[4- [(2R,6S)-2,6-dimethylmorpholin-4- yl]-1-piperidyl] methanone 1-283

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[3-(methylamino)azetidin- 1-yl]methanone 1-284

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-[(6-methyl-3-pyridyl)methyl]benzamide 1-285

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-(2-methyl-2- morpholino-propyl)benzamide 1-286

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-(3-morpholinopropyl)benzamide 1-287

4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-ethyl-N-(4-pyridylmethyl)benzamide 1-288

[4-[[8-[4-(4-chlorophenyl)- 4-(hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]phenyl]-[2-(4-pyridyl)pyrrolidin- 1-yl]methanone 1-289

2-[4-[[8-[4-(4- chlorophenyl)-4- (hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]pyrazol-1- yl]-1-[4-(morpholinomethyl)- 1-piperidyl]ethanone 1-290

formic acid; methyl 3- [4-[2-[4-[[8-[4-(4- chlorophenyl)-4-(hydroxymethyl)-1- piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]pyrazol-1- yl]acetyl]piperazin-1- yl]propanoate 1-291

2-[4-[[8-[4-(4- chlorophenyl)-4- (hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]pyrazol-1- yl]-1-[4-(methylamino)-1- piperidyl]ethanone 1-292

4-[[8-[(3aR,6aS)-5- hydroxy-5-phenyl- 1,3,3a,4,6,6a-hexahydrocyclopenta[c] pyrrol-2-yl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-293

4-[[8-(5-benzyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-294

4-[[8-[4-(4- chlorophenyl)-4- (cyanomethyl)cyclohexen-1-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-295

N-(3-morpholinopropyl)- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,4-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 1-296

3-[[1-[2-[4-[[8-[4-(4- chlorophenyl)-4- (hydroxymethyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]pyrazol-1- yl]acetyl]-4-piperidyl]-methyl- amino]propanenitrile 1-297

N-(1-isobutyl-4- piperidyl)-N-methyl- 2-[4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]pyrazol-1- yl]acetamide 1-298

4-[[8-[4-(2-amino-2- oxo-ethyl)-4-(4- chlorophenyl)-1- piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 1-299

4-[[8-[4-(4-chlorophenyl)- 4-[2-(methylamino)-2-oxo-ethyl]-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-300

4-[[8-[4-(4-chlorophenyl)- 4-[2-(dimethylamino)-2-oxo-ethyl]-1-piperidyl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 1-301

2-[4-(4-chlorophenyl)- 1-[2-[4-[methyl-(1- methyl-4-piperidyl)carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-4-piperidyl]acetic acid 1-302

4-[[8-(4-benzamido-4- methyl-1-piperidyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1- methyl-4- piperidyl)benzamide1-303

4-[[8-[4- (benzenesulfonamido)- 4-methyl-1-piperidyl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-1

ethyl 4-[2-[4-[methyl- (1-methyl-4-piperidyl) carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-2

cyclopropyl 4-[2-[4- [methyl-(1-methyl-4- piperidyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-3

4-[[8-[1-(3-hydroxy-3- methyl-butanoyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-4

4-[[8-[1-(2- cyclopropylacetyl)- 3,6-dihydro-2H- pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-5

4-[[8-[1-(3- cyanoazetidine-1- carbonyl)-3,6-dihydro- 2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-6

4-[[8-[1-(2- cyanoacetyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-7

cyanomethyl 4-[2-[4- [methyl-(1-methyl-4- piperidyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-8

4-[[8-(1-benzyl-3,6- dihydro-2H-pyridin-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide;hydrochloride 2-9

4-[[8-[1-(3- hydroxypropanoyl)- 3,6-dihydro-2H- pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-10

4-[[8-[1-[3- (dimethylamino) propanoyl]-3,6-dihydro- 2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1- methyl-4-piperidyl)benzamide; dihydrochloride 2-11

ethyl 4-[2-[4-[(2- methyl-2-morpholino- propyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-12

ethyl 4-[2-[4-[4- (dimethylamino) piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-13

ethyl 4-[2-[4-[2-(4- piperidyl)ethylcarbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-14

ethyl 4-[2-[4-[methyl(3- pyridylmethyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-15

ethyl 4-[2-[4-[2-(4- pyridyl)pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-16

ethyl 4-[2-[4-[4-(2- pyridylmethyl)piperidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-17

ethyl 4-[2-[4-[4-(2- pyridylmethyl)piperazine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-18

ethyl 4-[2-[4-(4- morpholinopiperidine- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-19

ethyl 4-[2-[4-[4-(3- pyridyl)piperazine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a[pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-20

ethyl 4-[2-[4-[6- (hydroxymethyl)-4- methyl-1,4-diazepane-1-carbonyl]anilino]- [1,2,4]triazolo-1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-21

ethyl 4-[2-[4-[2-(1- methyl-2- piperidyl)pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-22

ethyl 4-[2-[4-[2-[4- (dimethylamino)-6- methyl-2- pyridyl]pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-23

ethyl 4-[2-[4-(9- methyl-3-oxa-7,9- diazabicyclo[3.3.1] nonane-7-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-24

ethyl 4-[2-[4-(2- methylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-25

ethyl 4-[2-[4-(1-oxa-4,9- diazaspiro[5.5]undecane- 4-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-26

ethyl 4-[2-[4-(1-oxa-4,8- diazaspiro[5.5]undecane- 8-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-27

ethyl 4-[2-[4-(7- azaspiro[3.5]nonan-2- ylcarbamoyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-28

1-[4-[2-[4-(2,7- diazaspiro[4.4]nonane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-29

1-[4-[2-[4-(3,9- diazaspiro[5.5]undecane- 3-carbonyl)anilino]-[1,2,4]triazolo]1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-30

N-(morpholin-2- ylmethyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin- 4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-31

N-[2- (methylamino)ethyl]- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-32

N-(2-piperazin-1- ylethyl)-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-33

4,4,4-trifluoro-1-[4-[2- [4-[2-(hydroxymethyl) piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-34

1-[4-[2-[4-(1,8- diazaspiro[5.5]undecane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-35

1-[4-[2-[4-(2,7- diazaspiro[3.4]octane-2- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-36

N-methyl-N-(3- piperidyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin- 4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-37

4,4,4-trifluoro-1-[4-[2- [4-(9-oxa-3,7- diazabicyclo[3.3.1]nonane-3-carbonyl) anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-38

1-[4-[2-[4-[(3aS,6aS)- 1-methyl-2,3,3a,4,6,6a- hexahydropyrrolo[3,4-b]pyrrole-5- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-39

N-[(1-ethylpyrrolidin- 3-yl)methyl]-N-methyl- 4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-40

4,4,4-trifluoro-1-[4-[2- [4-(5-methyl-2,5- diazaspiro[3.4]octane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-41

N-[(4-methyl-2-pyridyl) methyl]-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-42

N-[(2-methyl-3-pyridyl) methyl]-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-43

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(4,4,4-trifluoro-3-methyl-butanoyl)- 3,6-dihydro-2H- pyridin-4-yl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-44

(1-methyl-4-piperidyl) 4-[[8-[1-(3,3- dimethylcyclo-butanecarboyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoate 2-45

4,4,4-trifluoro-1-[4-[2-[4- (3-morpholinopyrrolidine-1-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-46

4,4,4-trifluoro-1-[4-[2- [4-(4-pyrrolidin-1- ylpiperidine-1-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-47

N-[3-(2-methyl-1- piperidyl)propyl]-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-48

N-[2-(1- methylpyrrolidin-2- yl)ethyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-49

N-(1-cyclopentyl-4- piperidyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin- 4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-50

4,4,4-trifluoro-1-[4-[2- [4-[3-(5-methyl-2- pyridyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-51

1-[4-[2-[4-[3-[5- (dimethylamino)-2- pyridyl]piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin- 1-yl]-4,4,4-trifluoro- butan-1-one 2-52

4-[[8-[1-(cyanomethyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-53

4-[[8-[1-(3- methoxycyclo- butanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-54

4-[[8-[1-(3,3- dimethylbutanoyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-55

ethyl 4-[2-[4-[3- (methylamino)azetidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-56

ethyl 4-[2-[4-(3- morpholinopropyl- carbamoyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-57

ethyl 4-[2-[4-[2-(4- methylpiperazin-1-yl) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-58

ethyl 4-[2-[4-[(1- methylazetidin-3- yl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-59

ethyl 4-[2-[4-[methyl- [2-(2-pyridyl)ethyl] carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-60

ethyl 4-[2-[4-[(1-methyl- 4-piperidyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-61

ethyl 4-[2-[4-[methyl- [(1-methyl-3-piperidyl) methyl]carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-62

ethyl 4-[2-[4-[3-(4- pyridyl)pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-63

ethyl 4-[2-[4-[4-(2,6- dimethylmorpholin-4- yl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-64

ethyl 4-[2-[4-[4-(2- morpholinoethyl) piperazine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-65

ethyl 4-[2-[4-[(1- isopropylpyrrolidin-3- yl)methyl-methyl-carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-66

ethyl 4-[2-[4-(3- morpholinopyrrolidine- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-67

ethyl 4-[2-[4-[2-(5- methyl-2- pyridyl)pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-68

ethyl 4-[2-[4-(7- methyl-2,7- diazaspiro[3.4]octane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-69

ethyl 4-[2-[4-[[(3R)- quinuclidin-3- yl]carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-70

ethyl 4-[2-[4-(5,7- dihydropyrrolo[3,4- b]pyridine-6- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-71

ethyl 4-[2-[4-[4- (aminomethyl)-3- azabicyclo[2.1.1]hexane-3-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-72

ethyl 4-[2-[4- [(4aS,7aR)-3,4a,5,6,7,7a- hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine- 4-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-73

ethyl 4-[2-[4-[(1S,5R)- 5-amino-3- azabicyclo[3.1.0]hexane-3-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-74

ethyl 4-[2-[4-(3- aminoazetidine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-75

ethyl 4-[2-[4-(2,9- diazaspiro[5.5]undecane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-76

ethyl 4-[2-[4-[2- (aminomethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-77

ethyl 4-[2-[4-(2,6- diazaspiro[3.3]heptane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-78

ethyl 4-[2-[4-(2,7- diazaspiro[4.4]nonane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-79

ethyl 4-[2-[4-(2,8- diazaspiro[4.5]decane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-80

1-[4-[2-[4-[2- (aminomethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-81

1-[4-[2-[4-(2,7- diazaspiro[3.5]nonane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-82

4,4,4-trifluoro-1-[4-[2- [4-(1-oxa-4,8- diazaspiro[5.5]undecane-4-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-83

N-(1-oxa-8- azaspiro[4.5]decan-2- ylmethyl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-84

N-(4-piperidylmethyl)- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-85

4,4,4-trifluoro-1-[4-[2- [4-[3-(methylamino) pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-86

N-[2-(4-piperidyl)ethyl]- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-87

4,4,4-trifluoro-1-[4-[2- [4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrole-5-carbonyl) anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]butan-1-one 2-88

1-[4-[2-[4-[3-[2- (dimethylamino)ethyl] piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-89

1-[4-[2-[4-[4- [(dimethylamino)methyl]- 4-hydroxy-azepane-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-90

1-[4-[2-[4-[3-[6- (dimethylamino)-2- methyl-pyrimidin-4-yl]piperidine-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-91

1-[4-[2-[4-[4-[6- (dimethylamino)-2- pyridyl]piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-92

1-[4-[2-[4-[2-[4- (dimethylamino)-6- methyl-2- pyridyl]pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan- 1-one 2-93

4,4,4-trifluoro-1-[4-[2- [4-(8-methyl-2,8- diazaspiro[5.5]undecane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-94

ethyl 4-[2-[4-[(1- methyl-4-piperidyl) oxycarbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-95

4,4,4-trifluoro-1-[4-[2- [4-[4-(2-pyridylmethyl) piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-96

N-methyl-N-[2-(4- pyridyl)ethyl]-4-[[8- [1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-97

1-[4-[2-[4-[4- (dimethylamino) piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-98

4,4,4-trifluoro-1-[4-[2- [4-(4-methylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]butan-1-one 2-99

N-[3-(4-methylpiperazin- 1-yl)propyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-100

N-[2-(4-hydroxy-1- piperidyl)ethyl]-4-[[8- [1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-101

N-[2-(3-methyl-1- piperidyl)ethyl]-4-[[8- [1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-102

1-[4-[2-[4-[4-[2- (dimethylamino)ethyl] piperazine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-103

4,4,4-trifluoro-1-[4-[2- [4-[3-(1H-pyrrolo[2,3- b]pyridin-2-yl)piperidine-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-104

N-methyl-N-[[2-(3- pyridyl)phenyl]methyl]- 4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-105

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(tetrahydropyran-4-carbonyl)-3,6-dihydro- 2H-pyridin-4-yl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-106

N-methyl-4-[2-[4- [methyl-(1-methyl-4- piperidyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxamide; hydrochloride 2-107

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(tetrahydrofuran-3-carbonyl)-3,6-dihydro- 2H-pyridin-4-yl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide; hydrochloride 2-108

2,2,2-trifluoroethyl 4- [2-[4-[methyl-(1- methyl-4-piperidyl)carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-109

N-methyl-4-[[8-[1-(3- methylbutanoyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-(1-methyl-4-piperidyl)benzamide 2-110

ethyl 4-[2-[4-[(1,1- dimethyl-2-morpholino- ethyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-111

ethyl 4-[2-[4-[2-(1- methylpyrrolidin-2- yl)ethylcarbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-112

ethyl 4-[2-[4-(2- piperazin-1- ylethylcarbamoyl) anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-113

ethyl 4-[2-[4-(3- piperidylcarbamoyl) anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-114

ethyl 4-[2-[4-(2- piperidylmethylcarbamoyl) anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-115

ethyl 4-[2-[4-[3- (dimethylcarbamoyl) azetidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-116

ethyl 4-[2-[4-[2-(1- methyl-4- piperidyl)ethylcarbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-117

ethyl 4-[2-[4-[(1- benzylpyrrolidin-3- yl)-methyl- carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-118

ethyl 4-[2-[4-[3- (diethylamino)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-119

ethyl 4-[2-[4-[methyl- [2-(4-pyridyl)ethyl] carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-120

ethyl 4-[2-[4-(8- methyl-5-oxa-2,8- diazaspiro[3.5]nonane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-121

ethyl 4-[2-[4-[4-(4- pyridyl)piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-122

ethyl 4-[2-[4- [(3aS,6aS)-1-methyl- 2,3,3a,4,6,6a- hexahydropyrrolo[3,4-b]pyrrole-5- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-123

ethyl 4-[2-[4-(7- methyl-9-oxa-3,7- diazabicyclo[3.3.1]nonane-3-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-124

ethyl 4-[2-[4-[(4- methyl-2-pyridyl) methylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-125

ethyl 4-[2-[4- (2,3,5,5,6,7,8,8a- octahydropyrido[4,3- b][1,4]oxazine-4-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-126

ethyl 4-[2-[4- (2,3,3a,4,6,6a- hexahydro-1H- pyrrolo[3,4-c]pyrrole-5-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-127

ethyl 4-[2-[4-[(4aR,7aR)- 3,4a,5,6,7,7a-hexahydro- 2H-pyrrolo[3,4-b][1,4]oxazine-4- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-128

ethyl 4-[2-[4-(1,7- diazaspiro[3.5]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-129

ethyl 4-[2-[4-(piperazine- 1-carbonyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-130

ethyl 4-[2-[4-[3- (aminomethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-131

ethyl 4-[2-[4-(1,8- diazaspiro[5.5]undecane- 8-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-132

ethyl 4-[2-[4-(2,8- diazaspiro[5.5]undecane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-133

ethyl 4-[2-[4-(2-amino-7- azaspiro[3.5]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-134

ethyl 4-[2-[4-(1-oxa-4,8- diazaspiro[5.5]undecane- 4-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-135

ethyl 4-[2-[4-(2,8- diazaspiro[4.5]decane- 8-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-136

1-[4-[2-[4-(2,8- diazaspiro[4.5]decane- 8-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-137

N-(3-piperidyl)-4-[[8- [1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-138

N-[(3S)-3-piperidyl]- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-139

1-[4-[2-[4-[(4aS,7aR)- 3,4a,5,6,7,7a-hexahydro- 2H-pyrrolo[3,4-b][1,4]oxazine-4- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-140

4,4,4-trifluoro-1-[4-[2- [4-[3-(3- piperidyl)indoline-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-141

N-methyl-N-(8- quinolylmethyl)-4-[[8- [1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-142

3-[4-[4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino] benzoyl]piperazin-1-yl]propanenitrile 2-143

4,4,4-trifluoro-1-[4-[2- [4-[2-(5-methyl-2- pyridyl)pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-144

4,4,4-trifluoro-1-[4-[2- [4-[6-(hydroxymethyl)-4- methyl-1,4-diazepane-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-145

4,4,4-trifluoro-1-[4-[2- [4-[2-(3- pyridyl)pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-146

1-[4-[2-[4-(5,7- dihydropyrrolo[3,4- b]pyridine-6- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-147

N-[2-(4-methyl-1- piperidyl)ethyl]-4-[[8- [1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-148

N-[(6-methyl-3- pyridyl)methyl]-4-[[8- [1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-149

4,4,4-trifluoro-1-[4-[2- [4-[2-(1-methyl-4- piperidyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-150

N-cyclopropyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-151

1-[4-[2-[4- (1,3,4,6,7,8,9,9a- octahydropyrido[1,2- a]pyrazine-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-152

N-methyl-N-[2-(2- pyridyl)ethyl]-4-[[8- [1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-153

4,4,4-trifluoro-1-[4-[2- [4-[4-(2-hydroxyethyl) piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-154

4,4,4-trifluoro-1-[4-[2- [4-[2-(2- pyridyl)morpholine-4-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-155

4,4,4-trifluoro-1-[4-[2- [4-[4-(1H-pyrrolo-2,3-b]pyridin-2-yl)piperidine- 1-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-156

4,4,4-trifluoro-1-[4-[2- [4-[4-(2- pyridyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-157

1-[4-[2-[4-[4-(2,6- dimethylmorpholin-4- yl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-158

1-[4-[2-[4-[(3S)-3- (dimethylamino) pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-159

4,4,4-trifluoro-1-[4-[2- [4-[3-(4-methylpiperazine-1-carbonyl)azetidine-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-160

4-[[8-[1-(2,2- dimethylcyclopropane- carbonyl)-3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-161

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(2,2,3,3-tetramethylcyclopropane- carbonyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-162

4-[[8-[1-(1,1-dioxo- 1,4-thiazinane-4- carbonyl)-3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-163

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(3,3,3-trifluoropropanoyl)- 3,6-dihydro-2H- pyridin-4-yl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-164

4-[[8-[1-(3-hydroxy-3- methyl- cyclobutanecarbonyl)- 3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-165

ethyl 4-[2-[4-[3- (aminomethyl)azetidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-166

ethyl 4-[2-[4-[3-(2- pyridyl)piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-167

ethyl 4-[2-[4-[2-(2,6- dimethylmorpholin-4-yl) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-168

ethyl 4-[2-[4-[4-(2- hydroxyethyl)piperazine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-169

ethyl 4-[2-[4-[2- (dimethylamino) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-170

ethyl 4-[2-[4-[1-(6- methyl-2-pyridyl) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-171

ethyl 4-[2-[4- [cyclopropyl(2- pyridylmethyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-172

ethyl 4-[2-[4-[2-(4-pyridyl) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-173

ethyl 4-[2-[4-[methyl- [(3-methyl-2-pyridyl) methyl]carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-174

ethyl 4-[2-[4-[ethyl(4- pyridylmethyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 1-175

ethyl 4-[2-[4-(7- methyl-2,7- diazaspiro[3.5]nonane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 1-176

ethyl 4-[2-[4-(5- methyl-2,5- diazaspiro[3.4]octane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-177

ethyl 4-[2-[4-[(2- methyl-3-pyridyl) methylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-178

ethyl 4-[2-[4-[(5- methyl-3-pyridyl) methylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-179

ethyl 4-[2-[4-[2-(4- methyl-1-piperidyl) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-180

ethyl 4-[2-[4-(9-oxa-3,7- diazabicyclo[3.3.1]nonane-3-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-181

ethyl 4-[2-[4-(3,9- diazaspiro[5.5]undecane- 3-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-182

ethyl 4-[2-[4-(1,9- diazaspiro[4.6]undecane- 9-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-183

ethyl 4-[2-[4-(1,8- diazaspiro[4.5]decane- 8-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-184

ethyl 4-[2-[4-(2,7- diazaspiro[3.5]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-185

ethyl 4-[2-[4-(2,8- diazaspiro[3.5]nonane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-186

1-[4-[2-[4-(2,8- diazaspiro[3.5]nonane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-187

1-[4-[2-[4-(2,8- diazaspiro[4.5]decane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-188

N-(1-oxa-8- azaspiro[4.5]decan-3- yl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-189

N-(2-oxa-9- azaspiro[5.5]undecan- 3-ylmethyl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-190

4,4,4-trifluoro-1-[4-[2- [4-(1-oxa-4,8- diazaspiro[5.5]undecane-8-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-191

1-[4-[2-[4-(2,9- diazaspiro[5.5]undecane- 9-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-192

N-(3-piperidylmethyl)-4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-193

N-[2-(3- piperidyl)ethyl]-4-[[8- [1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-194

N-(2-aminoethyl)-4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-195

1-[4-[2-[4-(1,4- diazepane-1- carbonyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-196

4,4,4-trifluoro-1-[4-[2- [4-(3- methylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]butan-1-one 2-197

1-[4-[2-[4-(1,7- diazaspiro[3.5]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-198

1-[4-[2-[4-(1,8- diazaspiro[4.5]decane- 8-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-199

N-methyl-N-(2- pyridylmethyl)-4-[[8- [1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-200

1-[4-[2-[4-(3,4,6,7,8,8a- hexahydro-1H-pyrrolo[1,2- a]pyrazine-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-201

4,4,4-trifluoro-1-[4-[2- [4-(3-methyl-3,6- diazabicyclo[3.2.1]octane-6-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-202

1-[4-[2-[4-(4- cyclopropylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-203

4,4,4-trifluoro-1-[4-[2-[4- [4-[(1-methylimidazol-2-yl)methyl]piperazine- 1-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-204

1-[4-[2-[4-(6-acetyl-2,6- diazaspiro[3.3]heptane-2- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-205

4,4,4-trifluoro-1-[4-[2- [4-(7-methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane- 3-carbonyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-206

N-[(5-methyl-3- pyridyl)methyl]-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-207

1-[4-[2-[4-[3- (aminomethyl)azetidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-208

4,4,4-trifluoro-1-[4-[2- [4-[4-(4-methyl-1- piperidyl)piperidine-1-carbonyl]anilino]- [1,2,4]traizolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-209

N-(2-methoxyethyl)- N-(1-methyl-4- piperidyl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-210

4,4,4-trifluoro-1-[4-[2-[4- (4-morpholinopiperidine-1-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-211

1-[4-[2-[4-[3- (diethylamino)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-212

N-methyl-N-[2-(3- pyridyl)ethyl]-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-213

N-(2-methyl-2- morpholino-propyl)-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-214

N-[(1-methyl-2- piperidyl)methyl]-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-215

4,4,4-trifluoro-1-[4-[2- [4-[4-(5-methyl-2- pyridyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-216

N-[2-(6-methyl-2- pyridyl)ethyl]-4-[[8- [1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-217

1-[4-[2-[4-[3-[[6- (dimethylamino)pyrimidin- 4-yl]methyl]pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-218

4,4,4-trifluoro-1-[4-[2- [4-[3-[(5-methyl-2-pyridyl)methyl]pyrrolidine-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-219

N-ethyl-N-(4- pyridylmethyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-220

N-[2-(3- pyridyl)ethyl]-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-221

N-[2-(2-piperidyl) ethyl]-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-222

N-benzyl-4-[2-[4- [methyl-(1-methyl-4- piperidyl)carbamoyl] anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxamide 2-223

N-methyl-4-[[8-[1-(2- methylcyclopropane- carbonyl)-3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-(1-methyl-4- piperidyl)benzamide 2-224

methyl 4-[2-[4-[methyl- (1-methyl-4-piperidyl) carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-225

2,2-difluoroethyl 4-[2- [4-[methyl-(1-methyl-4- piperidyl)carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-226

ethyl 4-[2-[4-[2-(3- methyl-1-piperidyl) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-227

ethyl 4-[2-[4-[4-[2- (dimethylamino)ethyl] piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-228

ethyl 4-[2-[4-[2-(2- pyridyl)morpholine-4- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-229

ethyl 4-[2-[4-[2-(6- methyl-2-pyridyl) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-230

ethyl 4-[2-[4-[2- (methylamino) ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-231

ethyl 4-[2-[4-(pyrrolidin- 3-ylcarbamoyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-232

ethyl 4-[2-[4-[2-(3- pyridyl)piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-233

ethyl 4-[2-[4-(pyrrolidin- 2-ylmethylcarbamoyl) anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-234

ethyl 4-[2-[4-[3-(2- pyridylmethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-235

ethyl 4-[2-[4-[2-(2- pyridylmethyl)piperidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-236

ethyl 4-[2-[4-[4-(2- methoxyethyl)piperazine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-237

ethyl 4-[2-[4-[methyl-[2-(3- pyridyl)ethyl]carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-238

ethyl 4-[2-[4-[4- (cyclopropylmethyl) piperazine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-239

ethyl 4-[2-[4-[2-(2- pyridylmethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-240

ethyl 4-[2-[4-(2- methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5- carbonyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-241

ethyl 4-[2-[4-[4- hydroxy-4-(pyrrolidin- 1-ylmethyl)azepane-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-242

ethyl 4-[2-[4-[3-[2- (dimethylamino)ethyl] piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-243

ethyl 4-[2-[4-[2- (dimethylcarbamoyl)- 4-methyl-piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-244

ethyl 4-[2-[4-[(3aS,6aS)- 5-methyl-2,3,3a,4,6,6a- hexahydropyrrolo[2,3-c]pyrrole-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-245

ethyl 4-[2-[4-[(6-methyl-3- pyridyl)methylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-246

ethyl 4-[2-[4-[(3aS,6aS)- 3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[2,3-c]pyrrole- 1-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-247

ethyl 4-[2-[4-(1,8- diazaspiro[5.5]undecane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-248

ethyl 4-[2-[4-[(1R,5R)-3,6- diazabicyclo[3.2.0]heptane-3-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-249

ethyl 4-[2-[4-[(1-methyl-4- piperidyl)methylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-250

ethyl 4-[2-[4-[[(3S)-3- piperidyl]carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-251

ethyl 4-[2-[4-[4-(2- pyridyl)piperazine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-252

ethyl 4-[2-[4-(2,9- diazaspiro[5.5]undecane- 9-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-253

1-[4-[2-[4-(2,9- diazaspiro-[4.5]decane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-254

4,4,4-trifluoro-1-[4-[2- [4-(1-oxa-4,9- diazaspiro[5.5]undecane-4-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-255

N-pyrrolidin-3-yl-4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-256

1-[4-[2-[4-(3- aminoazetidine-1- carbonyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin- 1-yl]-4,4,4-trifluoro-butan-1-one 2-257

1-[4-[2-[4-(1,9- diazaspiro[4.5]decane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-258

1-[4-[2-[4-(1,8- diazaspiro[4.5]decane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-259

4,4,4-trifluoro-1-[4-[2- [4-(8-methyl-5-oxa-2,8- diazasprio[3.5]nonane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-260

1-[4-[2-[4-(4- cyclobutylpiperazine- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-261

N,N-dimethyl-2-(4- pyridyl)-1-[4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]pyrrolidine-2- carboxamide 2-262

4,4,4-trifluoro-1-[4-[2- [4-[3-(4-methylpiperazine-1-carbonyl)morpholine- 4-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-263

N-methyl-4-[[8-[1-(3- methylcyclobutane- carbonyl)-3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-(1-methyl-4- piperidyl)benzamide 2-264

(1-methyl-4-piperidyl) 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoate 2-265

4,4,4-trifluoro-1-[4-[2- [4-[2-(2-pyridylmethyl) piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-266

4,4,4-trifluoro-1-[4-[2- [4-(4-isobutylpiperazine- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]butan-1-one 2-267

N-methyl-N-(1- methylpyrrolidin-3- yl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-268

N-[2-(2,6- dimethylmorpholin-4- yl)ethyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-269

N-[2-(3,5-dimethyl-1- piperidyl)ethyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-270

N-[2-(4-methylpiperazin- 1-yl)ethyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-271

N-(3-morpholinopropyl)- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-272

N-cyclopropyl-N-(2- pyridylmethyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin- 4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-273

4,4,4-trifluoro-1-[4-[2-[4- [2-(4-pyridyl)pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-274

N-[2-(1-methyl-4- piperidyl)ethyl]-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-275

N,1-dimethyl-4-[4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]piperazine-2- carboxamide 2-276

N,4-dimethyl-1-[4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]piperazine-2- carboxamide 2-277

4,4,4-trifluoro-1-[4-[2- [4-[4-(3-pyridylmethyl) piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-278

4,4,4-trifluoro-1-[4-[2- [4-[4-(4-pyridyl)-1,4- diazepane-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-279

N-(2-hydroxyethyl)- N-(3-pyridylmethyl)- 4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-280

4,4,4-trifluoro-1-[4-[2- [4-[2-(3-pyridyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-281

4-[[8-[1- (cyclopentanecarbonyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-282

4-[[8-[1- (cyclobutanecarbonyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-283

oxetan-3-yl 4-[2-[4- [methyl-(1-methyl-4- piperidyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-284

N-methyl-N-(1-methyl-4- piperidyl)-4-[[8-(1-phenyl-3,6-dihydro-2H-pyridin-4- yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-285

4-[[8-[1-(4- cyanocyclohexane- carbonyl)-3,6-dihydro-2H- pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-286

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(2-oxa-6-azaspiro[3.3]heptane- 6-carbonyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-287

4-[[8-[1-(3- cyanopropanoyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-288

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-289

4-[[8-(1-butanoyl-3,6- dihydro-2H-pyridin-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-290

4-[[8-[1-(3,3- dimethylazetidine-1- carbonyl)-3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-291

ethyl 4-[2-[4-[3-(4- methylpiperazin-1-yl) propylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-292

ethyl 4-[2-[4-[methyl- (1-methylpyrrolidin-3- yl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-293

ethyl 4-[2-[4-[(1-methyl-3- piperidyl)methylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-294

ethyl 4-[2-[4-[2-(1- piperidyl)ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-295

ethyl 4-[2-[4-(3- morpholinopiperidine- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-296

ethyl 4-[2-[4-(pyrrolidin-3- ylmethylcarbamoyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-297

ethyl 4-[2-[4-[4-(3- pyridylmethyl)piperazine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-298

ethyl 4-[2-[4-[4-(4- methylpiperazin-1- yl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-299

ethyl 4-[2-[4-[4-(2- imidazol-1- ylethyl)piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-300

ethyl 4-[2-[4-[4-(4- methylpiperazine-1- carbonyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-301

ethyl 4-[2-[4-(4- isobutylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-302

ethyl 4-[2-[4-(4-pyrrolidin- 1-ylpiperidine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-303

ethyl 4-[2-[4-[cyclopropyl- (1-methyl-4-piperidyl) carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-304

ethyl 4-[2-[4-[4- [(dimethylamino)methyl]- 4-hydroxy-azepane-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-305

ethyl 4-[2-[4-[(1- ethylpyrrolidin-3- yl)methyl-methyl-carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-306

ethyl 4-[2-[4-(6- azaspiro[2.5]octan-2- ylmethylcarbamoyl) anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-307

ethyl 4-[2-[4-[4- (aminomethyl)piperidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-308

ethyl 4-[2-[4- (3,3a,4,5,6,6a-hexahydro- 2H-pyrrolo[2,3-c]pyrrole-1-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-309

ethyl 4-[2-[4-(1-oxa-4,9- diazaspiro[5.5]undecane- 9-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-310

ethyl 4-[2-[4-(1,7- diazaspiro[4.4]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-311

ethyl 4-[2-[4-(1,7- diazaspiro[4.4]nonane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-312

ethyl 4-[2-[4-(2,9- diazaspiro[4.5]decane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-313

1-[4-[2-[4-(2,3,3a,4,6,6a- hexahydro-1H- pyrrolo[3,4-c]pyrrole-5-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-314

1-[4-[2-[4-(2,7- diazaspiro[3.5]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-315

1-[4-[2-[4-(2-amino-7- azaspiro[3.5]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-316

N-(2-pyrrolidin-2- ylethyl)-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-317

N-(pyrrolidin-2- ylmethyl)-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-318

4,4,4-trifluoro-1-[4-[2- [4-(piperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]butan-1-one 2-319

4,4,4-trifluoro-1-[4-[2- [4-(2-methylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]butan-1-one 2-320

1-[4-[2-[4-[(3aS,6aS)- 3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[2,3-c]pyrrole- 1-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-321

1-[4-[2-[4-[(3aR,6aS)- 2,3,3a,4,6,6a- hexahydro-1H-pyrrolo[3,4-c]pyrrole- 5-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-322

N-(7-azaspiro[3.5]nonan- 2-yl)-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-323

1-[4-[2-[4-[(1S,5R)-5- amino-3- azabicyclo[3.1.0]hexane-3-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-324

4,4,4-trifluoro-1-[4-[2- [4-[2-(1-methyl-2- piperidyl)pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-325

N,N,1-trimethyl-4-[4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]piperazine- 2-carboxamide 2-326

1-[4-[2-[4-[(3aS,6aS)- 5-methyl-2,3,3a,4,6,6a- hexahydropyrrolo[2,3-c]pyrrole-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-327

4-isopropyl-N-methyl- 1-[4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]piperazine-2- carboxamide 2-328

4,4,4-trifluoro-1-[4-[2- [4-(7-methyl-2,7- diazaspiro[3.4]octane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-329

1-[4-[2-[4-(4- cyclohexylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-330

N-(1-isopropyl-4- piperidyl)-N-methyl- 4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-331

4,4,4-trifluoro-1-[4-[2- [4-[4-(2-methoxyethyl) piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-332

N-(1,2,2,6,6- pentamethyl-4- piperidyl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-333

N-(1,1-dimethyl-2- morpholino-ethyl)-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-334

N-[1-methyl-2-(1- piperidyl)ethyl]-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-335

N-(1-methyl-4-piperidyl)- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamaide 2-336

N-[2-(dimethylamino) ethyl]-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-337

N-[(1-methyl-3- piperidyl)methyl]-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-338

4,4,4-trifluoro-1-[4-[2-[4- [3-(4-pyridyl)pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-339

4,4,4-trifluoro-1-[4-[2-[4- (3-morpholinopiperidine-1-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-340

4,4,4-trifluoro-1-[4-[2- [4-[4-(tetrahydrofuran- 2-ylmethyl)piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-341

4,4,4-trifluoro-1-[4-[2-[4- [3-(2-pyridyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-342

1-benzyl-N-methyl-4- [4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]piperazine- 2-carboxamide 2-343

N-[2-(4-pyridyl)ethyl]-4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-344

4-[[8-(1-acetyl-3,6- dihydro-2H-pyridin-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-345

isobutyl 4-[2-[4-[methyl- (1-methyl-4-piperidyl) carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-346

tetrahydrofuran-3-yl 4-[2-[4-[methyl-(1- methyl-4-piperidyl)carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-347

4-[[8-[1-(3,3- dimethylcyclobutane- carbonyl)-3,6-dihydro-2H-pyridin-4-yl]- [1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-348

4-[[8-[1- (cyclohexanecarbonyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-349

propyl 4-[2-[4-[methyl- (1-methyl-4-piperidyl) carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-350

4-[[8-[1-(4- cyanocyclohexane- carbonyl)-3,6-dihydro-2H- pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-351

benzyl 4-[2-[4-[methyl- (1-methyl-4-piperidyl) carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-352

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-(1-pentanoyl-3,6-dihydro-2H-pyridin-4- yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-353

cyclopropylmethyl 4-[2- [4-[methyl-(1-methyl-4- piperidyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-354

ethyl 4-[2-[4-(4- methylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-355

ethyl 4-[2-[4-[[2- (dimethylamino)-1-methyl- ethyl]carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-356

ethyl 4-[2-[4-(1,4- diazepane-1- carbonyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-357

ethyl 4-[2-[4-[3- (methylamino)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-358

ethyl 4-[2-[4-[4-(2- pyridyl)piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-359

ethyl 4-[2-[4-[methyl(8- quinolylmethyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-360

ethyl 4-[2-[4-(4- piperidylcarbamoyl) anilino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1- carboxylate 2-361

ethyl 4-[2-[4-[methyl(4- pyridylmethyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-362

ethyl 4-[2-[4-(2- pyrrolidin-2- ylethylcarbamoyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-363

ethyl 4-[2-[4-[4- (tetrahydrofuran-2- ylmethyl)piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-364

ethyl 4-[2-[4-[2- methoxyethyl-(1-methyl- 4-piperidyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-365

ethyl 4-[2-[4-[(1- isopropyl-4-piperidyl)- methyl-carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-366

ethyl 4-[2-[4-(3-methyl-3,6- diazabicyclo[3.2.1]octane-6-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-367

ethyl 4-[2-[4-(4- cyclopropylpiperazine-1- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-368

ethyl 4-[2-[4-(4- cyclobutylpiperazine- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-369

ethyl 4-[2-[4-(8-methyl-2,8- diazaspiro[5.5]undecane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-370

ethyl 4-[2-[4-[2-(3- pyridyl)pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-371

ethyl 4-[2-[4-[(3aS,6aS)- 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrole- 5-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine- 1-carboxylate 2-372

ethyl 4-[2-[4-(2,7- diazaspiro[3.4]octane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-373

ethyl 4-[2-[4-(1,8- diazaspiro[4.5]decane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-374

ethyl 4-[2-[4-[2- aminoethyl(methyl) carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-375

ethyl 4-[2-[4-(2,6- diazaspiro[3.4]octane- 6-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-376

ethyl 4-[2-[4-(2,6- diazaspiro[4.5]decane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-377

1-[4-[2-[4-(1,7- diazaspiro[4.4]nonane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-378

1-[4-[2-[4-(2,6- diazaspiro[4.5]decane- 2-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-379

1-[4-[2-[4-(2,6- diazaspiro[3.4]octane- 6-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-380

4,4,4-trifluoro-1-[4-[2- [4-(1-oxa-4,9- diazaspiro[5.5]undecane-9-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-381

1-[4-[2-[4-(2,7- diazaspiro[4.5]decane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-382

1-[4-[2-[4-(2,9- diazaspiro[5.5]undecane-2- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-383

1-[4-[2-[4-(1,8- diazaspiro[5.5]undecane-8- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-384

1-[4-[2-[4-(1,9- diazaspiro[4.6]undecane-9- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-385

N-(2-piperidylmethyl)-4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-386

1-[4-[2-[4-(3,3a,4,5,6,6a- hexahydro-2H- pyrrolo[2,3-c]pyrrole-1-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-387

1-[4-[2-[4-[(3aS,6aS)- 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrole- 5-carbonly]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-388

N-(6-azaspiro[2.5]octan-2- ylmethyl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-389

N-methyl-N-[(1-methyl-3- piperidyl)methyl]-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-390

4,4,4-trifluoro-1-[4-[2- [4-[4-hydroxy-4- (pyrrolidin-1-ylmethyl)azepane-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-391

4,4,4-trifluoro-1-[4-[2- [4-(7-methyl-2,7- diazaspiro[3.5]nonane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-392

1-[4-[2-[4-(2,6- diazaspiro[3.3]heptane-2- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-393

4,4,4-trifluoro-1-[4-[2- [4-[4-(4-methylpiperazin-1- yl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-394

4,4,4-trifluoro-1-[4-[2- [4-[4-(3-pyridylmethyl) piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-395

4,4,4-trifluoro-1-[4-[2- [4-[4-(3- pyridyl)piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-396

4,4,4-trifluoro-1-[4-[2- [4-[2-(2-pyridylmethyl) pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-397

4,4,4-trifluoro-1-[4-[2-[4- [4-(2-pyridyl)piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-398

1-[4-[2-[4-[4- (cyclopropylmethyl) piperazine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-399

N-[2-(dimethylamino)-1- methyl-ethyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-400

N-cyclopropyl-N-(1- propyl-4-piperidyl)-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-401

N-[1-(6-methyl-2- pyridyl)ethyl]-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-402

N-methyl-N-(3- pyridylmethyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-403

1-[4-[2-[4-[3-(azepan- 1-yl)piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-404

4,4,4-trifluoro-1-[4-[2- [4-[4-(2-pyridylmethyl) piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-405

4,4,4-trifluoro-1-[4-[2- [4-[3-(3-pyridylmethyl) pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-406

N-[[4-(dimethylamino) phenyl]methyl]-N-methyl- 4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-407

N-methyl-N-(4- pyridylmethyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-408

4-[[8-(1-benzoyl-3,6- dihydro-2H-pyridin-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-409

4-[[8-[1- (cyclopropanecarbonyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-410

N-methyl-N-(1-methyl-4- piperidyl)-4-[[8-[1-(2- methylpropanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-411

4-[[8-[1-(3- methoxypropanoyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-412

N-methyl-4-[[8-[1-(4- methylpentanoyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-(1-methyl-4-piperidyl)benzamide 2-413

N-methyl-N-(1- methyl-4-piperidyl)-4- [[8-[1-(morpholine-4-carbonyl)-3,6-dihydro- 2H-pyridin-4-yl]- [1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-414

ethyl 4-[2-[4-[3- (dimethylamino) pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-415

ethyl 4-[2-[4-[(1-methyl-2- piperidyl)methylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-416

ethyl 4-[2-[4-[2-(3- piperidyl)ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-417

ethyl 4-[2-[4-[4-(2- cyanoethyl)piperazine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-418

ethyl 4-[2-[4-(3,4,6,7,8,8a- hexahydro-1H-pyrrolo[1,2- a]pyrazine-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-419

ethyl 4-[2-[4-[methyl(2- pyridylmethyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-420

ethyl 4-[2-[4-[(3S)-3- (dimethylamino) pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-421

ethyl 4-[2-[4-[3-(4- methylpiperazine-1- carbonyl)azetidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-422

ethyl 4-[2-[4-[2-(3- pyridyl)ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-423

ethyl 4-[2-[4-[2-(2- pyridyl)ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-424

ethyl 4-[2-[4-[3-(4- pyridylmethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-425

ethyl 4-[2-[4-(4- piperidylmethylcarbamoyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-426

ethyl 4-[2-[4-[3-(3- pyridylmethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-427

ethyl 4-[2-[4-(3- piperidylmethylcarbamoyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-428

ethyl 4-[2-[4-[2-(2- piperidyl)ethylcarbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1- carboxylate 2-429

ethyl 4-[2-[4-[4-(4- pyridyl)-1,4-diazepane-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-430

ethyl 4-[2-[4- (1,2,4,6,7,8,9,9a- octahydropyrido[1,2- a]pyrazine-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-431

ethyl 4-[2-[4-[3- (dimethylcarbamoyl)- 4-methyl-piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-432

ethyl 4-[2-[4-(6-acetyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-433

ethyl 4-[2-[4-[(1- methylpyrrolidin-3- yl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-434

ethyl 4-[2-[4-[[(1S,5R)-3- azabicyclo[3.1.0]hexan-6-yl]carbamoyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate 2-435

ethyl 4-[2-[4-[(3aR,6aS)- 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole- 5-carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1- carboxylate 2-436

ethyl 4-[2-[4-(1,9- diazaspiro[4.5]decane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-437

ethyl 4-[2-[4-(2,5- diazaspiro[3.5]nonane- 2-carbonyl)anilino]-[1,2,4]triazlo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-438

ethyl 4-[2-[4-[methyl(3- piperidyl)carbamoyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-439

ethyl 4-[2-[4-(2,7- diazaspiro[4.5]decane- 7-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridine-1-carboxylate 2-440

1-[4-[2-[4-(1,7- diazaspiro[4.4]nonane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-441

N-(2-aminoethyl)-N- methyl-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-442

N-(1-oxa-8- azaspiro[4.5]decan-3- ylmethyl)-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-443

1-[4-[2-[4-(2,8- diazaspiro[5.5]undecane-2- carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-444

N-(pyrrolidin-3- ylmethyl)-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-445

N-(4-piperidyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-446

1-[4-[2-[4-[4- (aminomethyl)piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-447

1-[4-[2-[4-[3- (aminomethyl)pyrrolidine- 1-carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-448

1-[4-[2-[4-[(4aR,7aR)- 3,4a,5,6,7,7a-hexahydro- 2H-pyrrolo[3,4-b][1,4]oxazine-4- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro-butan-1-one 2-449

1-[4-[2-[4-[(1R,5R)-3,6- diazabicyclo[3.2.0]heptane-3-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-450

1-[4-[2-[4-(1,9- diazaspiro[5.5]undecane- 1-carbonyl)anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-451

N-(azetidin-3-yl)-N- methyl-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-452

1-[4-[2-[4-[4- (aminomethyl)-3- azabicyclo[2.1.1]hexane-3-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-453

1-[4-[2-[4- (2,3,4a,5,6,7,8,8a- octahydropyrido[4,3- b][1,4]oxazine-4-carbonyl)anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]-4,4,4-trifluoro- butan-1-one 2-454

N-[(1R,5S)-3- azabicyclo[3.1.0]hexan- 6-yl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-455

N-[2-(1-piperidyl)ethyl]- 4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-456

4,4,4-trifluoro-1-[4-[2- [4-[4-(4-pyridyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-457

N,N,4-trimethyl-1-[4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]piperazine- 2-carboxamide 2-458

4,4,4-trifluoro-1-[4-[2- [4-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane- 7-carbonyl)anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-459

N-(1-methylpyrrolidin-3- yl)-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-460

N-methyl-N-(6- quinolylmethyl)-4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-461

4,4,4-trifluoro-1-[4-[2- [4-[4-(3-methyl-1- piperidyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-462

4,4,4-trifluoro-1-[4-[2- [4-[4-(2-imidazol-1- ylethyl)piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-463

N-[(1-isopropylpyrrolidin- 3-yl)methyl]-N-methyl- 4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-464

1-[4-[2-[4-[3- (dimethylamino) pyrrolidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-465

N-(2-morpholinoethyl)-4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-466

N-(2-pyrrolidin-1- ylethyl)-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-467

N-[(1-methyl-4- piperidyl)methyl]-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-468

4,4,4-trifluoro-1-[4-[2- [4-[4-(6-methyl-2- pyridyl)piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin- 1-yl]butan-1-one 2-469

N-[(3R)-quinuclidin- 3-yl]-4-[[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-470

N-methyl-1-(2- phenylethyl)-4-[4-[[8-[1- (4,4,4-trifluorobutanoyl)-3,6-dihydro-2H-pyridin- 4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzoyl]piperazine-2- carboxamide 2-471

4,4,4-trifluoro-1-[4-[2- [4-[3-(2-pyridylmethyl) pyrrolidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-472

1-[4-[2-[4-[3- [benzyl(methyl)amino] piperidine-1- carbonyl]anilino]-[1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1-yl]-4,4,4-trifluoro- butan-1-one 2-473

N-(1-benzylpyrrolidin- 3-yl)-N-methyl-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-474

4,4,4-trifluoro-1-[4-[2-[4- [4-(2-morpholinoethyl) piperazine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyridin-1- yl]butan-1-one 2-475

4,4,4-trifluoro-1-[4-[2-[4- [4-(4-methylpiperazine-1-carbonyl)piperidine-1- carbonyl]anilino]- [1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6- dihydro-2H-pyridin-1- yl]butan-1-one 2-476

N-methyl-N-[(3- methyl-2-pyridyl)methyl]- 4-[[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-477

N-methyl-N-[(1-methyl- 3,4-dihydro-2H-quinolin- 6-yl)methyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-478

N-[2-(2-pyridyl)ethyl]-4- [[8-[1-(4,4,4- trifluorobutanoyl)-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]benzamide 2-479

4-[[8-[1-(3,3- dimethylazetidin-1- yl)sulfonyl-3,6-dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-480

4-[[8-[1-(3,3- dimethylazetidine-1- carbonyl)-2,3,4,7-tetrahydroazepin-5- yl]-[1,2,4]trizaolo[1,5- a]pyridin-2-yl]amino]-N-methyl-N-(1-methyl- 4-piperidyl)benzamide 2-481

4-[[8-[1-(3,3- dimethylazetidine-1- carbonyl)-2,5- dihydropyrrol-3-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-482

4-[[8-[1-(2-cyano-1- methyl-ethyl)-3,6- dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]amino]- N-methyl-N-(1-methyl-4-piperidyl)benzamide 2-483

N-[[(2R)-1-methyl-2- piperidyl]methyl]-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-484

N-[2-[(3S)-3-methyl- 1-piperidyl]ethyl]-4- [[8-[1-(4,4,4-trifluorobutanoyl)-3,6- dihydro-2H-pyridin-4- yl]-[1,2,4]triazolo[1,5-a]pyridin-2- yl]amino]benzamide 2-485

N-[2-[(3R)-3-methyl-1- piperidyl]ethyl]-4-[[8-[1-(4,4,4-trifluorobutanoyl)- 3,6-dihydro-2H-pyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-2- yl]amino]benzamide 2-486

1-[4-[2-[4-[4-[(2R,6S)-2,6- dimethylmorpholin-4- yl]piperidine-1-carbonyl]anilino]- [1,2,4]triazolo[1,5- a]pyridin-8-yl]-3,6-dihydro-2H-pyrdin-1- yl]-4,4,4-trifluoro- butan-1-one 3-1

N-[8-4-(aminomethyl)-4- phenyl-1-piperidyl]- [1,2,4]triazolo[1,5-a]pyridin-2-yl] cyclopropanecarboxamide; hydrochloride

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Mixtures of particular diastereomeric compounds may beseparated, or enriched in one or more particular diastereomers, bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated, or enantiomerically enriched, using the sametechniques or others known in the art. Each of the asymmetric carbon ornitrogen atoms may be in the R or S configuration and both of theseconfigurations are within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined. Unless otherwise specified, if solid wedges ordashed lines are used, relative stereochemistry is intended.

Another aspect includes prodrugs of the compounds of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, including known amino-protecting and carboxy-protecting groupswhich are released, for example hydrolyzed, to yield the compound of thepresent invention under physiologic conditions.

The term “prodrug” refers to a precursor or derivative form of apharmaceutically active substance that is less efficacious to thepatient compared to the parent drug and is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). Prodrugs include, but are not limited to,phosphate-containing prodrugs, thiophosphate-containing prodrugs,sulfate-containing prodrugs, peptide-containing prodrugs, D-aminoacid-modified prodrugs, glycosylated prodrugs, β-lactam-containingprodrugs, optionally substituted phenoxyacetamide-containing prodrugs oroptionally substituted phenylacetamide-containing prodrugs, and5-fluorocytosine and 5-fluorouridine prodrugs.

A particular class of prodrugs are compounds in which a nitrogen atom inan amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidinogroup is substituted with a hydroxy group, an alkylcarbonyl (—CO—R)group, an alkoxycarbonyl (—CO—OR), or an acyloxyalkyl-alkoxycarbonyl(—CO—O—R—O—CO—R) group where R is a monovalent or divalent group, forexample alkyl, alkylene or aryl, or a group having the Formula—C(O)—O—CP1P2-haloalkyl, where P1 and P2 are the same or different andare hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In aparticular embodiment, the nitrogen atom is one of the nitrogen atoms ofthe amidino group of the compounds of Formula 0, Formula I or FormulaII. Prodrugs may be prepared by reacting a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, with an activated group, such as acyl groups, to bond, for example,a nitrogen atom in the compound to the exemplary carbonyl of theactivated acyl group. Examples of activated carbonyl compounds are thosecontaining a leaving group bonded to the carbonyl group, and include,for example, acyl halides, acyl amines, acyl pyridinium salts, acylalkoxides, acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxyacyl, fluorophenoxy acyl, and difluorophenoxy acyl. The reactions aregenerally carried out in inert solvents at reduced temperatures such as−78 to about 50° C. The reactions may also be carried out in thepresence of an inorganic base, for example potassium carbonate or sodiumbicarbonate, or an organic base such as an amine, including pyridine,trimethylamine, triethylamine, triethanolamine, or the like.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention, such as a compound ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or suitable freecarboxyl-containing compound of any of Examples 1-1 to 1-303, 2-1 to2-486 or 3-1, can be derivatized as an amide or alkyl ester. As anotherexample, compounds of the present invention comprising free hydroxygroups can be derivatized as prodrugs by converting the hydroxy groupinto a group such as, but not limited to, a phosphate ester,hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonylgroup, as outlined in Fleisher, D. et al., (1996) Improved oral drugdelivery: solubility limitations overcome by the use of prodrugsAdvanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxyand amino groups are also included, as are carbonate prodrugs, sulfonateesters and sulfate esters of hydroxy groups. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup can be an alkyl ester optionally substituted with groupsincluding, but not limited to, ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in J. Med. Chem., (1996), 39:10. More specific examplesinclude replacement of the hydrogen atom of the alcohol group with agroup such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,alpha-amino(C C₄)alkanoyl, arylacyl and alpha-aminoacyl, oralpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

“Leaving group” refers to a portion of a first reactant in a chemicalreaction that is displaced from the first reactant in the chemicalreaction. Examples of leaving groups include, but are not limited to,halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groupsinclude, but are not limited to, alkylsulfonyloxy groups (for examplemethyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy(triflate group)) and arylsulfonyloxy groups (for examplep-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylategroup)).

Synthesis of Janus Kinase Inhibitor Compounds

Compounds of the present invention may be synthesized by syntheticroutes described herein. In certain embodiments, processes well-known inthe chemical arts can be used, in addition to, or in light of, thedescription contained herein. The starting materials are generallyavailable from commercial sources such as Aldrich Chemicals (Milwaukee,Wis.) or are readily prepared using methods well known to those skilledin the art (e.g., prepared by methods generally described in Louis F.Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley,N.Y. (1967-1999 ed.), Beilsteins Handbuch der organischen Chemie, 4,Aufl. ed. Springer-Verlag, Berlin, including supplements (also availablevia the Beilstein online database)), or Comprehensive HeterocyclicChemistry, Editors Katrizky and Rees, Pergamon Press, 1984.

Compounds may be prepared singly or as compound libraries comprising atleast 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.Libraries of compounds may be prepared by a combinatorial ‘split andmix’ approach or by multiple parallel syntheses using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art. Thus according to a further aspect of the invention there isprovided a compound library comprising at least 2 compounds of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id,Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to2-486 or 3-1.

For illustrative purposes, reaction Schemes 1-24 depicted below provideroutes for synthesizing the compounds of the present invention as wellas key intermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used. Although somespecific starting materials and reagents are depicted in the Schemes anddiscussed below, other starting materials and reagents can besubstituted to provide a variety of derivatives or reaction conditions.In addition, many of the compounds prepared by the methods describedbelow can be further modified in light of this disclosure usingconventional chemistry well known to those skilled in the art.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups include acetyl,trifluoroacetyl, benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Other conversions commonly used in the synthesis of compounds of thepresent invention, and which can be carried out using a variety ofreagents and conditions, include the following:

-   (1) Reaction of a carboxylic acid with an amine to form an amide.    Such a transformation can be achieved using various reagents known    to those skilled in the art but a comprehensive review can be found    in Tetrahedron, 2005, 61, 10827-10852.-   (2) Reaction of a primary or secondary amine with an aryl halide or    pseudo halide, e.g., a triflate, commonly known as a    “Buchwald-Hartwig cross-coupling,” can be achieved using a variety    of catalysts, ligands and bases. A review of these methods is    provided in Comprehensive Organic Name Reactions and Reagents, 2010,    575-581.-   (3) A palladium cross-coupling reaction between an aryl halide and a    vinyl boronic acid or boronate ester. This transformation is a type    of “Suzuki-Miyaura cross-coupling,” a class of reaction that has    been thoroughly reviewed in Chemical Reviews, 1995, 95(7),    2457-2483.-   (4) The hydrolysis of an ester to give the corresponding carboxylic    acid is well known to those skilled in the art and conditions    include: for methyl and ethyl esters, the use of a strong aqueous    base such as lithium, sodium or potassium hydroxide or a strong    aqueous mineral acid such as HCl; for a tert-butyl ester, hydrolysis    would be carried out using acid, for example, HCl in dioxane or    trifluoroacetic acid (TFA) in dichloromethane (DCM).

Scheme 1 provides details of the reactions available for the preparationof compounds of the invention wherein R² of Formula 0 is of type (a).Compound (1-3) can be prepared from 3-bromo-2-aminopyridine (1-1)according to WO2009/155551, incorporated herein by reference, and mayundergo a Buchwald-Hartwig cross-coupling reaction with an aryl halide,an example of which would be ethyl 4-iodobenzoate, using a catalyst suchas tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃) or palladium(II) acetate (Pd(OAc)₂), a phosphine ligand such as4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) and a basesuch as caesium carbonate. Where (1-1) has additional substituents inthe pyridine ring, a compound (1-3) having additional substitution inthe 6-membered ring can be prepared. A wide range of substituted3-bromo-2-aminopyridines are known in the literature and arecommercially available and the preparations of compounds (i), (ii) and(iii) from the corresponding substituted 3-bromo-2-aminopyridine, usinganalogous chemistry to that shown for (1-3) in Scheme 1, are describedin WO2011/092272, WO2010/141796 and WO2010/141796, respectively, eachincorporated herein by reference.

An ester (1-4) can be hydrolysed to the corresponding carboxylic acid(1-5) using standard conditions which would be dependent upon theparticular ester group present. An amide (1-6) may be formed from (1-5)using an amine R¹R²NH under standard coupling conditions, for exampleusing (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (HATU) in the presence of a base such asN,N-diisopropylethylamine (DIPEA). Intermediate (1-6) may also beprepared directly from (1-3) and amide (1-7) using the same chemistriesin an alternative sequence. Compound (1-6) may then be converted into(1-9) by reaction with a cyclic secondary amine (1-8) via aBuchwald-Hartwig cross-coupling using a palladium catalyst such asPd₂(dba)₃ and a suitable ligand such as Xantphos in the presence of abase providing structures of Formula 0 with R² being of type (a).Alternatively, ester (1-4) may undergo a palladium catalysed aminationwith (1-8) to give (1-10). The ester moiety in (1-10) may then behydrolysed under standard conditions to give an acid (1-11) which thenmay be reacted with an amine R¹R²NH to give a compound (1-9).

In Scheme 1, R³ or R⁴ may be further elaborated. For example, in Scheme2, where R⁴ is CH₂CN (2-1), the nitrile group may be converted into thecorresponding primary amide (2-2). Reagents suitable for this conversioninclude acetaldoxime in the presence of palladium (II) acetate andtriphenylphosphine. The nitrile group in (2-1) may also be hydrolysed tothe corresponding carboxylic acid (2-3) which in turn can be treatedwith an amine R⁴R⁵NH under standard amidation conditions to providecompounds of type (2-4).

Where R⁴ in the compounds of Scheme 1 is an ester, exemplified bystructure (3-1) of Scheme 3, this group may be hydrolysed under standardconditions to give an acid of type (3-2). Common amidation conditionsmay then be used to prepare an amide (3-3) from (3-2) and a suitableamine R³R⁴NH.

The cyclic secondary amine (1-8) of Scheme 1, in which R⁴ is hydroxyland R³ is an optionally substituted alkyl, aryl or heteroaryl group, maybe prepared according to Scheme 4. Reaction of a suitably nitrogenprotected aminoketone (4-1) with either a Grignard reagent or anorganolithium may provide the alcohol (4-2). Deprotection of the aminenitrogen to give amine (4-3) can then be achieved using conditionsdesigned to remove the protecting group of choice.

Schemes 5 to 8 and 18 to 24 describe the methods that can be used toprepare other cyclic secondary amines (1-8), of Scheme 1, which arerequired for preparation of examples where the required amine (1-8) ishitherto unknown in the scientific literature. The methods use standardreactions known to those skilled in the art.

Scheme 5 provides a preparation of 1-oxa-3,7-diazaspiro[4.4]nonan-2-one(5-4). Starting with the commercially available aminoalcohol (5-1),reaction with triphosgene, or one of its equivalents, followed byremoval of the benzyl group by catalytic hydrogenation can provide(5-3).

Scheme 6 describes routes to secondary amines (1-8) of Scheme 1 in whichR³ is phenyl or substituted phenyl and R⁴ is either cyano (6-6) orhydroxymethyl (6-5). Treatment of a cyanomethylbenzene with a base suchas sodium hydride and subsequent reaction of the resultant anion withcommercially available (6-1) may provide (6-2). The deprotection of(6-2) under acidic conditions gives amine (6-6). Reduction of thenitrile in intermediate (6-2), using diisobutylaluminium hydride forexample, affords the aldehyde (6-3) which may be further reduced to thealcohol (6-4) by treatment with sodium borohydride. Boc deprotectionwill give the amine (6-5).

Scheme 7 shows methods that can be used to prepare a secondary amine(1-8) of Scheme 1 in which R³ is hydrogen and R⁴ is2-(2-methoxyethoxy)pyridin-4-ylmethoxy (7-4). Treatment of Boc-protected4-piperidinol (7-2) with a base such as potassium tert-butoxide, andreaction with commercially available4-(chloromethyl)-2-(2-methoxyethoxy)pyridine (7-1) in the presence of aniodide source such as terabutylammonium iodide gives (7-3). Treatment ofthe latter with acid leads to Boc deprotection and provides amine (7-4)

Scheme 8 describes routes to amines 1-8 from Scheme 1 in which R³ is aphenyl or substituted phenyl and R⁴ is either cyanomethyl (8-6),hydroxyethyl (8-9) or cyanoethyl (8-12). The synthesis of intermediatesof type (8-5) is described in Journal of Medicinal Chemistry, 2011, 54(11), 3756-3767 and Boc deprotection can be achieved by treatment withacid. Reduction of the nitrile in (8-5) firstly to the aldehyde (8-7)using diisobutylaluminium hydride and then to the alcohol (8-8) withsodium borohydride provides (8-8) which can be Boc-deprotected in acidto give (8-9). Conversion of the alcohol (8-8) into the correspondingmethanesulfonate ester (8-10) and subsequent reaction with a cyanidesource such as sodium cyanide provides (8-11). Boc-deprotection of(8-11) results in the formation of amine (8-12).

Analogous chemistries to those described in Scheme 1 may be used preparecompounds of the invention wherein R² of Formula 0 is of type (b) byreplacing the cyclic secondary amine (1-8) with an amine of type (iv).Here, R³/R⁴ may be modified further using standard chemistries.

Scheme 9 indicates how other compounds of the invention may be preparedwherein R² of Formula 0 is of type (d). Ester (1-4) or amide (1-6) fromScheme 1 may undergo a palladium catalysed Buchwald-Hartwigcross-coupling with a diamine (9-1). Where R³ in (9-5), or indeed (9-3),is a protecting group, it may be removed under standard conditions andthe resulting amine (9-6) may be further modified through alkylation,arylation, acylation, sulfonylation etc.

Scheme 10 indicates how other compounds of the invention may be preparedwherein R² of Formula 0 is of type (c). Either ester (1-4) or amide(1-6) from Scheme 1 may be reacted with a suitable boronate ester orboronic acid in a Suzuki-Miyaura cross-coupling reaction. An example ofa palladium catalyst that may be useful in such a transformation wouldbe bis(triphenylphosphine)palladium (II) dichloride (Pd(PPh₃)₂Cl₂).Where R³ in intermediate (10-2) or (10-5) is a protecting group, it maybe removed under standard conditions to give amines (10-3) and (10-6),respectively. The latter may be further modified using standardchemistries, examples of which are given in Scheme 11. The ester maylater be converted into an amide if required.

By hydrogenation of the double bond in either compound (10-3) or (10-6),or in the preceding intermediates (10-2), (10-4) and (10-5) of Scheme10, other compounds of the invention may be prepared wherein R² ofFormula 0 is of type (e). The amine (11-1) in Scheme 11 may be furthermodified using standard acylation, alkylation, arylation andsulfonylation chemistries. These specifically include: (i) Reaction witha chloroformate in the presence of a base such as triethylamine to givethe corresponding carbamate; (ii) Alkylation with an alkyl halide in thepresence of a base or reductive alkylation using an aldehyde or ketoneand a reducing agent such as sodium triacetoxyborohydride; (iii)Acylation by reaction with a carboxylic acid and an amide coupling agentsuch as HATU or by reaction with an acid chloride in the presence of abase; (iv) Hydrogenation using hydrogen gas over a palladium catalyst;(v) Formation of an activated carbamate by reaction with 4-nitrophenylchloroformate and then further reaction with an amine to form a urea;(vi) Arylation using an arylboronic acid or boronate ester in thepresence of copper (II) acetate; (vii) Formation of a sulphonamide byreaction with a sulfonyl chloride in the presence of a base. The productof hydrogenation (11-2) can be subjected to reactions (i), (ii), (iii),(v), (vi) and (vii) in order to form compounds (11-3) wherein R² of isof type (e).

Scheme 12 indicates how other compounds of the invention may be preparedwherein R² of Formula 0 is of type (f). Either ester (1-4) or amide(1-6) from Scheme 1 may be reacted with a suitable boronate ester (12-1)or boronic acid in a Suzuki-Miyaura cross-coupling to give (12-2) and(12-4), respectively. The palladium catalyst may be for examplePd(PPh₃)₂Cl₂ or Pd₂(dba)₃ and the base may be sodium or cesium carbonateor sodium tert-butoxide. Groups R³ and R⁴ may be further modified usingstandard chemistries.

Scheme 13 shows an alternative approach available for the preparation ofcompounds of the invention. The Group R¹ may be incorporated into a2-aminopyridine (13-1) prior to formation of the bicycle (13-3) whichmay then be further modified using the methodologies described herein.This method is of particular use in the synthesis of compounds ofFormula 0 wherein R² is of type (g). A method for preparing compounds(13-1) from 3-bromo-2-aminopyridine is available in WO2012/020848,incorporated herein by reference.

An alternative route to compounds of structure (g) wherein R² is OAr isdescribed in Scheme 14. An intermediate (14-1) can be reacted with aphenol using a copper catalyst. Specifically, (14-1) can be convertedinto a compound of type (14-2) by heating with the appropriate phenol inthe presence of picolinic acid, copper (I) iodide and a base such aspotassium phosphate tribasic or caesium carbonate.

During the synthesis of compounds of the invention it may be convenientto convert an intermediate carboxylic acid, exemplified by structure(15-1) in Scheme 15, into an ester (15-2) wherein R² is different tothat present in the original intermediate (1-5) of Scheme 1. This can beachieved using standard esterification protocols such as the use of EDCin combination with HOBt as shown in Scheme 15.

Analogous chemistries to those described in Scheme 1 to 15 may be usedprepare compounds of the invention wherein R² of Formula 0 is of type(b) by replacing the cyclic analogues where Ar¹ present in Formula 0 isreplaced by a 1,3 or 1,2-disubstituted phenyl or a di-substitutedheteroaryl group.

An alternative method for the introduction of an aryl or heteroaryl ringAr¹ in structure (I) is given in Scheme 16. In this case, the8-substituted [1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1-3) from Scheme1 may be converted into the 2-iodo analogue (16-1) via the diazoniumsalt which is formed in situ by the action of sodium nitrite andp-toluenesulfonic acid and which is converted into (16-1) by potassiumiodide. Intermediate (16-1) can then undergo a Buchwald-Hartwigcross-coupling with an aryl or heteroaryl amine. One such example of thelatter would be aminopyrazole (16-2).

Reaction of Intermediate (1-3) from Scheme 1 with an acid chloride suchas cyclopropanecarbonyl chloride in the presence of pyridine may giverise to key intermediate (17-1) for the preparation of compounds ofFormula (II) as described in Scheme 17. Analogous chemistries to thosedescribed in Schemes 1 to 15 may be used to further elaborate the bromosubstituent into groups Q¹ of Formula (II).

Scheme 18 describes routes to amines 1-8 from Scheme 1 in which R³ is aphenyl or substituted phenyl and R⁴ is methyl acetamido. Reduction ofthe nitrile (6-2) using a metal catalyzed reduction under an atmosphereof hydrogen with a reagent such as Raney Nickel may be used to affordthe methylamino intermediate (18-1) which may be protected as theacetamide using acetic anhydride and a base to afford acetamideintermediate (18-2). Boc deprotection under standard acidic conditionsmay be used to afford the amine (18-3).

Scheme 19 describes routes to amines 1-8 from Scheme 1 in which R³ isethyl-(2,2,2-trifluoroethyl)amine and R⁴ is hydroxymethyl. Deprotonationadjacent to the nitrile of commercially available (19-1), using a basesuch as LDA, followed by treatment with BOM-Cl affords the benzyloxyintermediate (19-2). The nitrile of intermediate (18-2) may be reducedto the aldehyde (18-3) using a suitable reducing agent such as DIBAl-H.The aldehyde may then be converted to the amine (18-4) usingtrifluoroethylamine and a reducing agent such as sodiumcyanoborohydride. Hydrogenation of the benzyloxy intermediate (19-4)using palladium catalysis under an atmosphere of hydrogen may be used toprepare the hydroxymethyl intermediate (19-5). Removal of the Bocprotecting group under standard conditions may be used to give the amine(19-6).

Scheme 20 describes routes to amines 1-8 from Scheme 1 in which R³ is a4-difluoromethyl substituted phenyl and R⁴ is hydroxymethyl. Treatmentof commercially available 4-bromobenzylcyanide with a base such assodium hydride and reaction of the resultant anion with the commerciallyavailable alkylating agent (6-1) may be used to prepare intermediate(20-1). The ester (20-2) may be prepared from Intermediate (20-1) usinga carbonylation reaction with a palladium catalyst such as Pd(dppf)Cl₂under an atmosphere of carbon monoxide. Reduction of the ester inintermediate (20-2) using, for example, DIBAl-H affords the alcohol(20-3) which may then be oxidized to the aldehyde (20-4) using anoxidant such as DMP. The aldehyde of (20-4) may be converted to thedifluoromethyl intermediate (20-5) using a reagent such as DAST.Reduction of the nitrile in Intermediate (20-5), using DIBAl-H forexample, may afford the aldehyde (20-6) which may be further reduced tothe alcohol (20-7) by treatment with sodium borohydride. Bocdeprotection under standard conditionds may be used to prepare the amine(20-8).

Scheme 21 describes routes to amines 1-8 from Scheme 1 in which R³ is aphenyl or substituted phenyl and R⁴ is a propane-1,2-diol. Treatment ofmethanesulfonate ester (8-10) with a base such as potassiumtert-butoxide may provide the alkene (21-1). Intermediate (21-1) may betreated with an oxidant such as osmium tetroxide to afford diol (21-2).Boc deprotection under standard conditions may be used to give the amine(21-3).

Scheme 22 describes a route to the amine (22-4) in which R³ is acycloalkyl and R⁴ is either cyanomethyl. Conjugate addition toIntermediate (8-2) using reagents such as a Grignard and copper(I)iodide may be used to prepare intermediate (22-1). Hydrolysis of theester in Intermediate (22-1) with a base such as potassium hydroxidefollowed by decarboxylation using a reagent such as copper (I) oxide maybe used to give Intermediate (22-3). Boc deprotection under standardconditions may be used to give the amine (22-4)

Scheme 23 describes routes to amines 1-8 from Scheme 1 in which R³ is aphenyl or substituted phenyl and R⁴ is a propionic acid ethyl ester.Hydrolysis of the nitrile (8-6) under acidic conditions with a reagentsuch as HCl in acetic acid gives the acid (23-1). Esterification of theacid with an alcohol such as ethanol under acidic conditions gives theester (23-2). Boc deprotection under standard conditions may be used togive the amine (23-3).

Scheme 24 describes routes to amines 1-8 from Scheme 1 in which R³ is aphenyl or substituted phenyl and R⁴ is either carboxylic acid (24-6),difluoroethyl (24-7), 2-hydroxyethyl (24-8), 2-hydroxytrifluoroethyl(24-9), or methoxymethyl (24-10). Hydrolysis of the nitrile (6-2) underacidic conditions with a reagent such as HCl in acetic acid may be usedto afford the acid (24-1). Treatment of the aldehyde (8-7) with areagent such as DAST may be used to afford the difluoroethylintermediate (24-2). Addition of a methyl Grignard such as methylmagnesium bromide to the aldehyde (6-3) may be used to afford the2-hydroxyethyl intermediate (24-3). Treatment of the aldehyde (6-3) witha reagent such as CF3-TMS in the presence of a base such as potassiumcarbonate may be used to give the trifluorohydroxy intermediate (24-4).Treatment of the alcohol (6-4) with a base such as sodium hydride in thepresence of methyl iodide may be used to afford the methyl ether (24-5).Standard conditions may be used to deprotect Intermediates (24-1) to(24-5) to afford the amines (24-6) to (24-10).

Scheme 25 describes a route to compounds of the invention wherein Ar¹ isa pyrazole. Ester (16.2) from Scheme 16 may undergo a palladiumcatalysed Buchwald-Hartwig cross-coupling with an amine (1-8). Where R¹in (25-1) is a protecting group, it may be removed under standardconditions and the resulting acid (25-2) may be further modified throughan amide coupling to afford amides of the Formula 25-3.

Scheme 26 describes an alterntive route towards compounds where Ar¹ is apyrazole. The 2-iodo analogue (16-1) may undergo a palladium catalysedBuchwald-Hartwig cross-coupling with a protected aminopyrazole, such asthe SEM amino pyrazole, to afford compounds of Formula (26-1). Compoundsof Formula (26-1) may then undergo a further palladium catalysedBuchwald-Hartwig cross-coupling with an amine (1-8) to afford compoundsof Formula (26-2). The pyrazole protecting group in (26-2) may then beremoved under standard conditions to afford compounds of Formula (26-3)which may be subsequently alkylated with a suitable alkylating agent andbase to afford compounds of formula (25-1). Compounds of Formula (25-1)may be further modified as in Scheme 25 to afford amides of Formula(25-3).

Methods of Separation

In each of the exemplary Schemes it may be advantageous to separatereaction products from one another or from starting materials. Thedesired products of each step or series of steps is separated orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization or trituration from a solvent orsolvent mixture, distillation, sublimation, or chromatography.Chromatography can involve any number of methods including, for example:reverse-phase and normal phase; size exclusion; ion exchange;supercritical fluid; high, medium, and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (SMB) and preparative thin or thick layer chromatography, aswell as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. Example separation methods include boilingpoint, and molecular weight in distillation and sublimation, presence orabsence of polar functional groups in chromatography, stability ofmaterials in acidic and basic media in multiphase extraction, and thelike. One skilled in the art will apply techniques most likely toachieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn or supercritical fluid chromatography.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S., Stereochemistry of OrganicCompounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically purechiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetriccompounds bearing acidic functionality, such as carboxylic acid andsulfonic acid. The diastereomeric salts may be induced to separate byfractional crystallization or ionic chromatography. For separation ofthe optical isomers of amino compounds, addition of chiral carboxylic orsulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelicacid, or lactic acid can result in formation of the diastereomericsalts.

Alternatively, the substrate to be resolved is reacted with oneenantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons,Inc., New York, 1994, p. 322).

Diastereomeric compounds can be formed by reacting asymmetric compoundswith enantiomerically pure chiral derivatizing reagents, such as menthylderivatives, followed by separation of the diastereomers and hydrolysisto yield the pure or enriched enantiomer. A method of determiningoptical purity involves making chiral esters, such as a menthyl ester,e.g., (−) menthyl chloroformate in the presence of base, or Mosherester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111,incorporated herein by reference). By method (3), a racemic mixture oftwo enantiomers can be separated by chromatography using a chiralstationary phase (Chiral Liquid Chromatography W. J. Lough, Ed., Chapmanand Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378(1990)). Enriched or purified enantiomers can be distinguished bymethods used to distinguish other chiral molecules with asymmetriccarbon atoms, such as optical rotation and circular dichroism. Theabsolute stereochemistry of chiral centers and enatiomers can bedetermined by x-ray crystallography.

Positional isomers, for example E and Z forms, of compounds of Formula0, Formula I or Formula II, and intermediates for their synthesis, maybe observed by characterization methods such as NMR and analytical HPLC.For certain compounds where the energy barrier for interconversion issufficiently high, the E and Z isomers may be separated, for example bypreparatory HPLC.

Pharmaceutical Compositions and Administration

The compounds with which the invention is concerned are JAK kinaseinhibitors, such as JAK1 inhibitors, and are useful in the treatment ofseveral diseases, for example, inflammatory diseases, such as asthma.

Accordingly, another embodiment provides pharmaceutical compositions ormedicaments containing a compound of the invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of anyof Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, and a pharmaceuticallyacceptable carrier, diluent or excipient, as well as methods of usingthe compounds of the invention to prepare such compositions andmedicaments.

In one example, a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Igor II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, may be formulated by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed into agalenical administration form. The pH of the formulation depends mainlyon the particular use and the concentration of compound, but typicallyranges anywhere from about 3 to about 8. In one example, a compound ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any ofExamples 1-1 to 1-303, 2-1 to 2-486 or 3-1, is formulated in an acetatebuffer, at pH 5. In another embodiment, the compounds of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, are sterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart. In general, the daily dose range for oral administration will liewithin the range of from about 0.001 mg to about 100 mg per kg bodyweight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1to 10 mg per kg, in single or divided doses. In general, the daily doserange for inhaled administration will lie within the range of from about0.1 μg to about 1 mg per kg body weight of a human, preferably 0.1 μs to50 μg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

The compounds of the invention, such as a compound of Formula 0, I, Ia,Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples 1-1 to1-303, 2-1 to 2-486 or 3-1, may be administered by any suitable means,including oral, topical (including buccal and sublingual), rectal,vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal, inhaled and epidural andintranasal, and, if desired for local treatment, intralesionaladministration. Parenteral infusions include intramuscular, intravenous,intraarterial, intraperitoneal, or subcutaneous administration. In someembodiments, inhaled administration is employed.

The compounds of the present invention, such as a compound of Formula 0,I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples1-1 to 1-303, 2-1 to 2-486 or 3-1, may be administered in any convenientadministrative form, e.g., tablets, powders, capsules, lozenges,granules, solutions, dispersions, suspensions, syrups, sprays, vapors,suppositories, gels, emulsions, patches, etc. Such compositions maycontain components conventional in pharmaceutical preparations, e.g.,diluents (e.g., glucose, lactose or mannitol), carriers, pH modifiers,buffers, sweeteners, bulking agents, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, perfuming agents, flavoring agents, other known additives aswell as further active agents.

Suitable carriers and excipients are well known to those skilled in theart and are described in detail in, e.g., Ansel, Howard C., et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R.,et al. Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Forexample, carriers include solvents, dispersion media, coatings,surfactants, antioxidants, preservatives (e.g., antibacterial agents,antifungal agents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, gels, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, pp 1289-1329, 1990). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.Exemplary excipients include dicalcium phosphate, mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate or combinations thereof. A pharmaceutical composition maycomprise different types of carriers or excipients depending on whetherit is to be administered in solid, liquid or aerosol form, and whetherit need to be sterile for such routes of administration.

For example, tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers, for example, lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example, magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample, methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavoring or coloring agents.

For topical application to the skin, a compound may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

Compounds of the invention, such as a compound of Formula 0, I, Ia, Ib,Ic, Id, Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303,2-1 to 2-486 or 3-1, may also be formulated for inhalation, for example,as a nasal spray, or dry powder or aerosol inhalers. For delivery byinhalation, the compound is typically in the form of microparticles,which can be prepared by a variety of techniques, includingspray-drying, freeze-drying and micronisation. Aerosol generation can becarried out using, for example, pressure-driven jet atomizers orultrasonic atomizers, such as by using propellant-driven meteredaerosols or propellant-free administration of micronized compounds from,for example, inhalation capsules or other “dry powder” delivery systems.

By way of example, a composition of the invention may be prepared as asuspension for delivery from a nebulizer or as an aerosol in a liquidpropellant, for example, for use in a pressurized metered dose inhaler(PMDI). Propellants suitable for use in a PMDI are known to the skilledperson, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl₂F₂) andHFA-152 (CH₄F₂ and isobutane).

In some embodiments, a composition of the invention is in dry powderform, for delivery using a dry powder inhaler (DPI). Many types of DPIare known.

Microparticles for delivery by administration may be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles may be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they may have a massmedian aerodynamic diameter of, for example, greater than 90 μm.

In the case of an aerosol-based formulation, an example is:

Compound of the invention* 24 mg/canister Lecithin, NF Liq. Conc. 1.2mg/canister Trichlorofluoromethane, NF 4.025 g/canisterDichlorodifluoromethane, NF 12.15 g/canister. *Such as a compound ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any ofExamples 1-1 to 1-303, 2-1 to 2-486 or 3-1.

A compound, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-4816or 3-1, may be dosed as described depending on the inhaler system used.In addition to the compound, the administration forms may additionallycontain excipients as described above, or, for example, propellants(e.g., Frigen in the case of metered aerosols), surface-activesubstances, emulsifiers, stabilizers, preservatives, flavorings, fillers(e.g., lactose in the case of powder inhalers) or, if appropriate,further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g., Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inthe case of powder inhalers in particular, a number of technicalsolutions are available (e.g., Diskhaler®, Rotadisk®, Turbohaler® or theinhalers, for example, as described in U.S. Pat. No. 5,263,475,incorporated herein by reference). Additionally, compounds of theinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, may be delivered in multi-chamber devices thus allowing fordelivery of combination agents.

The compound, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie,If, Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to2-486 or 3-1, may also be administered parenterally in a sterile medium.Depending on the vehicle and concentration used, the compound can eitherbe suspended or dissolved in the vehicle. Advantageously, adjuvants suchas a local anaesthetic, preservative or buffering agents can bedissolved in the vehicle.

Methods of Treatment with and Uses of Janus Kinase Inhibitors

The compounds of the present invention, such as a compound of Formula 0,I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples1-1 to 1-303, 2-1 to 2-486 or 3-1, inhibit the activity of a Januskinase, such as JAK1 kinase. For example, a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, inhibits the phosphorylation of signal transducers and activatorsof transcription (STATs) by JAK1 kinase as well as STAT mediatedcytokine production. Compounds of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or acompound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, areuseful for inhibiting JAK1 kinase activity in cells through cytokinepathways, such as IL-6, IL-15, IL-7, IL-2, IL-4, IL-9, IL-10, IL-13,IL-21, G-CSF, IFNalpha, IFNbeta or IFNgamma pathways. Accordingly, inone embodiment is provided a method of contacting a cell with a compoundof the present invention, such as a compound of Formula 0, I, Ia, Ib,Ic, Id, Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303,2-1 to 2-486 or 3-1, to inhibit a Janus kinase activity in the cell(e.g., JAK1 activity).

The compounds of the present invention, such as compounds of Formula 0,I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples1-1 to 1-303, 2-1 to 2-486 or 3-1, can be used for the treatment ofimmunological disorders driven by aberrant IL-6, IL-15, IL-7, IL-2,IL-4, IL9, IL-10, IL-13, IL-21, G-CSF, IFNalpha, IFNbeta or IFNgammacytokine signaling.

Accordingly, one embodiment includes compounds of the present invention,such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, ora compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, for usein therapy.

In some embodiments, there is provided use a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, in the treatment of an inflammatory disease. Further provided isuse of a compound of the present invention, such as a compound ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any ofExamples 1-1 to 1-303, 2-1 to 2-486 or 3-1, for the preparation of amedicament for the treatment of an inflammatory disease, such as asthma.Also provided is a compound of the present invention, such as a compoundof Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of anyof Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, for use in the treatmentof an inflammatory disease, such as asthma.

Another embodiment includes a method of preventing, treating orlessening the severity of a disease or condition, such as asthma,responsive to the inhibition of a Janus kinase activity, such as JAK1kinase activity, in a patient. The method can include the step ofadministering to a patient a therapeutically effective amount of acompound of the present invention, such as a compound of Formula 0, I,Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples 1-1to 1-303, 2-1 to 2-486 or 3-1. In one embodiment, the disease orcondition responsive to the inhibition of a Janus kinase, such as JAK1kinase, is asthma.

In one embodiment, the disease or condition is cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer'sdisease, cystic fibrosis, viral disease, autoimmune diseases,atherosclerosis, restenosis, psoriasis, rheumatoid arthritis,inflammatory bowel disease, asthma, allergic disorders, inflammation,neurological disorders, a hormone-related disease, conditions associatedwith organ transplantation (e.g., transplant rejection),immunodeficiency disorders, destructive bone disorders, proliferativedisorders, infectious diseases, conditions associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, CNS disorders or amyeloproliferative disorder.

In one embodiment, the inflammatory disease is rheumatoid arthritis,psoriasis, asthma, inflammatory bowel disease, contact dermatitis ordelayed hypersensitivity reactions. In one embodiment, the autoimmunedisease is rheumatoid arthritis, lupus or multiple sclerosis.

In one embodiment, the cancer is breast, ovary, cervix, prostate,testis, penile, genitourinary tract, seminoma, esophagus, larynx,gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicularcarcinoma, melanoma, lung, small cell lung carcinoma, non-small celllung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of thelung, colon, pancreas, thyroid, papillary, bladder, liver, biliarypassage, kidney, bone, myeloid disorders, lymphoid disorders, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivarygland, pharynx, small intestine, colon, rectum, anal, renal, prostate,vulval, thyroid, large intestine, endometrial, uterine, brain, centralnervous system, cancer of the peritoneum, hepatocellular cancer, headcancer, neck cancer, Hodgkin's or leukemia.

In one embodiment, the disease is a myeloproliferative disorder. In oneembodiment, the myeloproliferative disorder is polycythemia vera,essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia(CML).

Another embodiment includes the use of a compound of the presentinvention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If,Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or3-1, for the manufacture of a medicament for the treatment of a diseasedescribed herein (e.g., an inflammatory disorder, an immunologicaldisorder or cancer).

Combination Therapy

The compounds of the present invention, such as a compound of Formula 0,I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples1-1 to 1-303, 2-1 to 2-486 or 3-1, may be employed alone or incombination with other agents for treatment. The second compound of apharmaceutical composition or dosing regimen typically has complementaryactivities to the compound of this invention such that they do notadversely affect each other. Such agents are suitably present incombination in amounts that are effective for the purpose intended. Thecompounds may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially. Such sequential administration maybe close or remote in time.

For example, other compounds may be combined with compounds with whichthe invention is concerned for the prevention and treatment ofinflammatory diseases, such as asthma. Thus the present invention isalso concerned with pharmaceutical compositions comprising atherapeutically effective amount of a compound of the invention and oneor more other therapeutic agents. Suitable therapeutic agents for acombination therapy with compounds of the invention include, but are notlimited to: an adenosine A2A receptor antagonist; an anti-infective; anon-steroidal Glucocorticoid Receptor (GR Receptor) agonist; anantioxidant; a β2 adrenoceptor agonist; a CCR1 antagonist; a chemokineantagonist (not CCR1); a corticosteroid; a CRTh2 antagonist; a DPIantagonist; a formyl peptide receptor antagonist; a histone deacetylaseactivator; a chloride channel hCLCA1 blocker; an epithelial sodiumchannel blocker (ENAC blocker; an inter-cellular adhesion molecule 1blocker (ICAM blocker); an IKK2 inhibitor; a JNK inhibitor; acyclooxygenase inhibitor (COX inhibitor); a lipoxygenase inhibitor; aleukotriene receptor antagonist; a dual β2 adrenoceptor agonist/M3receptor antagonist (MABA compound); a MEK-1 inhibitor; amyeloperoxidase inhibitor (MPO inhibitor); a muscarinic antagonist; ap38 MAPK inhibitor; a phosphodiesterase PDE4 inhibitor; aphosphatidylinositol 3-kinase γ inhibitor (PI3-kinase γ inhibitor); aperoxisome proliferator activated receptor agonist (PPAR γ agonist); aprotease inhibitor; a retinoic acid receptor modulator (RAR γmodulator); a statin; a thromboxane antagonist; or a vasodilator.

In addition, compounds of the invention, such as a compound of Formula0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any of Examples1-1 to 1-303, 2-1 to 2-486 or 3-1, may be combined with: (1)corticosteroids, such as alclometasone dipropionate, amelometasone,beclomethasone dipropionate, budesonide, butixocort propionate,biclesonide, blobetasol propionate, desisobutyrylciclesonide,dexamethasone, dtiprednol dicloacetate, fluocinolone acetonide,fluticasone furoate, fluticasone propionate, loteprednol etabonate(topical) or mometasone furoate; (2) β2-adrenoreceptor agonists such assalbutamol, albuterol, terbutaline, fenoterol, and long actingβ2-adrenoreceptor agonists such as metaproterenol, isoproterenol,isoprenaline, salmeterol, indacaterol, formoterol (including formoterolfumarate), arformoterol, carmoterol, GSK 642444, GSK 159797, GSK 159802,GSK 597501, GSK 678007, or AZD3199; (3) corticosteroid/long acting β2agonist combination products such as salmeterol/fluticasone propionate(Advair®, also sold as Seretide®), formoterol/budesonide (Symbicort®),formoterol/fluticasone propionate (Flutiform®), formoterol/ciclesonide,formoterol/mometasone furoate, indacaterol/mometasone furoate,indacaterol/QAE 397, GSK 159797/GSK 685698, GSK 159802/GSK 685698, GSK642444/GSK 685698, GSK 159797/GSK 870086, GSK 159802/GSK 870086, GSK642444/GSK 870086, or arformoterol/ciclesonide; (4) anticholinergicagents, for example, muscarinic-3 (M3) receptor antagonists such asipratropium bromide, tiotropium bromide, aclidinium (LAS-34273),NVA-237, GSK 233705, darotropium, GSK 573719, GSK 961081, QAT 370, orQAX 028; (5) dual pharmacology M3-anticholinergic/β2-adrenoreceptoragonists such as GSK961081; (6) leukotriene modulators, for example,leukotriene antagonists such as montelukast, zafirulast or pranlukast orleukotriene biosynthesis inhibitors such as zileuton or BAY-1005, orLTB4 antagonists such as amelubant, or FLAP inhibitors such as GSK2190914, AM-103; (7) phosphodiesterase-IV (PDE-IV) inhibitors (oral orinhaled), such as roflumilast, cilomilast, oglemilast, ONO-6126,tetomilast, tofimilast, UK 500,001, or GSK 256066; (8) antihistamines,for example, selective histamine-1 (H1) receptor antagonists such asfexofenadine, citirizine, loratidine or astemizole or dual H1/H3receptor antagonists such as GSK 835726, or GSK 1004723; (9) antitussiveagents, such as codeine or dextramorphan; (10) a mucolytic, for example,N-acetyl cysteine or fudostein; (11) a expectorant/mucokineticmodulator, for example, ambroxol, hypertonic solutions (e.g., saline ormannitol) or surfactant; (12) a peptide mucolytic, for example,recombinant human deoxyribonoclease I (dornase-alpha and rhDNase) orhelicidin; (13) antibiotics, for example azithromycin, tobramycin oraztreonam; (14) non-selective COX-1/COX-2 inhibitors, such as ibuprofenor ketoprofen; (15) COX-2 inhibitors, such as celecoxib and rofecoxib;(16) VLA-4 antagonists, such as those described in WO97/03094 andWO97/02289, each incorporated herein by reference; (17) TACE inhibitorsand TNF-α inhibitors, for example anti-TNF monoclonal antibodies, suchas Remicade® and CDP-870 and TNF receptor immunoglobulin molecules, suchas Enbrel®; (18) inhibitors of matrix metalloprotease, for exampleMMP-12; (19) human neutrophil elastase inhibitors, such as ONO-6818 orthose described in WO2005/026124, WO2003/053930 and WO06/082412, eachincorporated herein by reference; (20) A2b antagonists such as thosedescribed in WO2002/42298, incorporated herein by reference; (21)modulators of chemokine receptor function, for example antagonists ofCCR3 and CCR8; (22) compounds which modulate the action of otherprostanoid receptors, for example, a thromboxane A₂ antagonist; DP1antagonists such as MK-0524, CRTH2 antagonists such as ODC9101 andAZD1981 and mixed DP1/CRTH2 antagonists such as AMG 009; (23) PPARagonists including PPAR alpha agonists (such as fenofibrate), PPAR deltaagonists, PPAR gamma agonists such as pioglitazone, rosiglitazone andbalaglitazone; (24) methylxanthines such as theophylline oraminophylline and methylxanthine/corticosteroid combinations such astheophylline/budesonide, theophylline/fluticasone propionate,theophylline/ciclesonide, theophylline/mometasone furoate andtheophylline/beclometasone dipropionate; (25) A2a agonists such as thosedescribed in EP1052264 and EP1241176; (26) CXCR2 or IL-8 antagonistssuch as SCH 527123 or GSK 656933; (27) IL-R signalling modulators suchas kineret and ACZ 885; and (28) MCP-1 antagonists such as ABN-912.

In some embodiments, the compounds of the present invention, such as acompound of Formula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or acompound of any of Examples 1-1 to 1-303, 2-1 to 2-486 or 3-1, can beused in combination with one or more additional drugs, for exampleanti-hyperproliferative, anti-cancer, cytostatic, cytotoxic,anti-inflammatory or chemotherapeutic agents, such as those agentsdisclosed in U.S. Publ. Appl. No. 2010/0048557, incorporated herein byreference. A compound of the present invention, such as a compound ofFormula 0, I, Ia, Ib, Ic, Id, Ie, If, Ig or II, or a compound of any ofExamples 1-1 to 1-303, 2-1 to 2-486 or 3-1, can be also used incombination with radiation therapy or surgery, as is known in the art.

Articles of Manufacture

Another embodiment includes an article of manufacture (e.g., a kit) fortreating a disease or disorder responsive to the inhibition of a Januskinase, such as a JAK1 kinase. The kit can comprise:

(a) a first pharmaceutical composition comprising a compound of thepresent invention, such as a compound of Formula 0, I, Ia, Ib, Ic, Id,Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1 to2-486 or 3-1; and

(b) instructions for use.

In another embodiment, the kit further comprises:

(c) a second pharmaceutical composition, such as a pharmaceuticalcomposition comprising an agent for treatment as described above, suchas an agent for treatment of an inflammatory disorder, or achemotherapeutic agent.

In one embodiment, the instructions describe the simultaneous,sequential or separate administration of said first and secondpharmaceutical compositions to a patient in need thereof.

In one embodiment, the first and second compositions are contained inseparate containers. In another embodiment, the first and secondcompositions are contained in the same container.

Containers for use include, for example, bottles, vials, syringes,blister pack, etc. The containers may be formed from a variety ofmaterials such as glass or plastic. The container includes a compound ofthe present invention, such as a compound of Formula 0, I, Ia, Ib, Ic,Id, Ie, If, Ig or II, or a compound of any of Examples 1-1 to 1-303, 2-1to 2-486 or 3-1, or composition thereof, which is effective for treatingthe condition and may have a sterile access port (for example thecontainer may be an intravenous solution bag or a vial having a stopperpierceable by a hypodermic injection needle). The label or packageinsert indicates that the compound or composition is used for treatingthe condition of choice, such as asthma or cancer. In one embodiment,the label or package inserts indicates that the compound or compositioncan be used to treat a disorder. In addition, the label or packageinsert may indicate that the patient to be treated is one having adisorder characterized by overactive or irregular Janus kinase activity,such as overactive or irregular JAK1 activity. The label or packageinsert may also indicate that the compound or composition can be used totreat other disorders.

Alternatively, or additionally, the kit may further comprise a second(or third) container comprising a pharmaceutically acceptable buffer,such as bacteriostatic water for injection (BWFI), phosphate-bufferedsaline, Ringer's solution or dextrose solution. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, and syringes.

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare othercompounds of the present invention, and alternative methods forpreparing the compounds are within the scope of this invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the invention.

Examples

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as defined by the claims.

Abbreviations

-   -   AcOH Acetic acid    -   BINAP 2,2 ‘-Bis(diphenylphosphino)-1,1’-binaphthalene    -   n-BuLi n-Butyllithium solution    -   t-BuOH tert-butanol    -   t-BuOK Potassium tert-butoxide    -   t-BuONa Sodium tert-butoxide    -   CDCl₃ Deuterated chloroform    -   CD₃OD Deuterated methanol    -   CO Carbon monoxide    -   Cs₂CO₃ Cesium carbonate    -   CuI Copper (I) iodide    -   Cu₂O Copper (I) oxide    -   DIBAl-H Diisobutylaluminum hydride    -   DIPEA Diisopropylethylamine    -   DMF Dimethylformamide    -   DMSO Dimethylsulfoxide    -   DMSO-d6 Deuterated dimethylsulfoxide    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   g Gram    -   HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate)    -   HCl Hydrochloric acid    -   HCOOH Formic acid    -   HM-N Isolute HM-N is a modified form of diatomaceous earth    -   KOAc Potassium acetate    -   KOH Potassium hydroxide    -   K₃PO₄ Potassium phosphate tribasic    -   L Litre    -   MeOH Methanol    -   mg Milligram    -   mL Millilitre    -   mmol Millimoles    -   Ms₂O Methanesulfonic anhydride    -   NaBH₃CN Sodium cyanoborohydride    -   NaBH₄ Sodium borohydride    -   NaCN Sodium cyanide    -   NaHCO₃ Sodium hydrogen carbonate    -   NaOH Sodium hydroxide    -   Na₂SO₄ Sodium sulfate    -   NH₃.H₂O 0.880 ammonia solution    -   NH₂OH.HCl Hydroxylamine hydrochloride    -   NH₄HCO₃ Ammonium bicarbonate    -   NH₄OAc Ammonium acetate    -   Pd/C Palladium on carbon    -   Pd₂(dba)₃ Tris(dibenzylidineacetone)palladium(0)    -   Pd(dppf)Cl₂        [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium-(II),        complex with dichloromethane    -   Pd(OAc)₂ Palladium (II) acetate    -   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)    -   PTSA p-Toluene sulfonic acid    -   r,t or rt or r t Room temperature    -   SCX-2 ISOLUTE® Si-Propylsulfonic acid    -   THF Tetrahydrofuran    -   TFA Trifluoroacetic acid    -   TLC Thin layer chromatography    -   XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene    -   X-phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

NMR Analytical Methods

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz) spectrometer with a 400 4NUC 5 mm probe, a Bruker AvanceDRX400 (400 MHz) spectrometer with a PABBO 5 mm probe. Chemical shiftsare expressed in ppm relative to tetramethylsilane. The followingabbreviations have been used: br=broad signal, s=singlet, d=doublet,dd=double doublet, t=triplet, q=quartet, m=multiplet.

LCMS Analytical Methods

High Pressure Liquid Chromatography—Mass Spectrometry (LCMS) experimentsto determine retention times (RT) and associated mass ions wereperformed using one of the following methods with either UV detectormonitoring at 220 nm and 254 nm or evaporative light scatteringdetection, and mass spectrometry scanning 110-800 amu in ESI+ ionizationmode.

Method 1

Experiments were performed on a Waters ZMD single quadrupole massspectrometer with an electrospray source operating in positive andnegative ion mode linked to a Waters 1525 LC system. Detection wasachieved using a UV diode array detector and a Sedex 85 evaporativelight scattering detector. The LC column was a Phenomenex Luna 3 micronC18(2) 30×4.6 mm. The flow rate was 2 mL/minute. The initial solventsystem was 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for 0.5 minutefollowed by a gradient up to 5% solvent A and 95% solvent B over thenext 4 minutes. The final solvent system was held constant for a further1 minute.

Method 2

Experiments were performed on a Waters Micromass ZQ2000 singlequadrupole mass spectrometer with an electrospray source operating inpositive and negative ion mode linked to a Waters Acquity UPLC system.Detection was achieved using a UV PDA detector. The flow rate was 2mL/minute. The initial solvent system was 95% water containing 0.1%formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid(solvent B) for 0.4 minute followed by a gradient up to 5% solvent A and95% solvent B over the next 5.6 minutes. The final solvent system washeld constant for a further 0.8 minute.

Method 3

Experiments were performed on a Waters Acquity UPLC with a Shim-packXR-ODS column (50×3.0 mm Acquity BEH C18, 2.2 μm particle size), elutionwith solvent A: Water/0.05% TFA; solvent B: Acetonitrile/0.05% TFA at40° C. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.201.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD

MS ionisation method—ESI+

Method 4

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (30×2.1 mm Xtimate™-C18, 3 μm particle size),elution with solvent A: water+0.038% trifluoroacetic acid; solvent B:acetonitrile+0.02% trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.01 1.5 95 5 0.70 1.5 5 95 1.1 1.55 95 1.11 1.5 95 5

Method 5

Experiments were performed on a HPLC Agilent 1200 with an Agilent SB C18column (30×2.1 mm Agilent SB C18, 1.8 μm particle size), elution withsolvent A: Water/0.05% TFA; solvent B: Acetonitrile/0.05% TFA at 25° C.Gradient:

Gradient - Time flow ml/min % A % B 0.00 0.4 97 3 0.3 0.4 95 3 6.8 0.4 595 10 0.4 97 3

Detection—UV 254 nm

MS ionisation method—ESI+

Method 6

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (50×3 mm Xtimate™-C18, 2.2 μm particle size),elution with solvent A: water+0.05% trifluoroacetic acid; solvent B:acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.101.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD

Method 7

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (50×3 mm Xtimate™-C18, 2.2 μm particle size),elution with solvent A: water+0.05% trifluoroacetic acid; solvent B:acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.201.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD

Method 8

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (50×3 mm Xtimate™-C18, 2.2 μm particle size),elution with solvent A: water+0.05% trifluoroacetic acid; solvent B:acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.201.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD

Method 9

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (50×3 mm Xtimate™-C18, 2.2 μm particle size),elution with solvent A: water+0.05% formic acid; solvent B:acetonitrile+0.05% formic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 1.20 1.0 0 100 2.201.0 0 100 2.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD

Method 10

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (50×3 mm Xtimate™-C18, 2.2 μm particle size),elution with solvent A: water+0.1% formic acid; solvent B:acetonitrile+0.05% formic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.00 1.0 0 100 3.101.0 0 100 3.20 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD

Method 11

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (50×3 mm Xtimate™-C18, 2.2 μm particle size),elution with solvent A: water+0.04% Ammonia; solvent B: acetonitrile.Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 95 5 1.20 1.2 0 100 2.201.2 0 100 2.30 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD

Method 12

Experiments were performed on a SHIMADZU 20A HPLC with aC18-reverse-phase column (30×2.1 mm Xtimate™-C18, 3 μm particle size),elution with solvent A: water+0.05% trifluoroacetic acid; solvent B:acetonitrile+0.05% trifluoroacetic acid. Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 1.10 1.0 0 100 1.601.0 0 100 1.70 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD

Example 1aN-methyl-4-(8-(4-methyl-4-phenylpiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-(1-methylpiperidin-4-yl)benzamide(Example 1-1 of Table I)

A degassed mixture of4-((8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(200 mg, 0.45 mmol), 4-methyl-4-phenylpiperidine (158.2 mg, 0.90 mmol),tBuONa (130.2 mg, 1.36 mmol), BINAP (56.4 mg, 0.09 mmol) andtris(dibenzylideneacetone)palladium (0) (41.4 mg, 0.045 mmol) in toluene(8 mL) was heated at 130° C. under nitrogen for 8 h. When the startingmaterial was consumed, the reaction mixture was added to water (10 mL)and extracted with dichloromethane (50 mL×3). The organic layers weredried over Na₂SO₄ and concentrated to give the residue which waspurified by prep-HPLC to give Example 1-1 (see Table I) (120 mg, 56.1%).

¹H NMR (400 MHz, CD₃OD) δ 8.74 (d, J=6.8 Hz, 1H), 7.95 (d, J=8.0 Hz,1H), 7.77 (d, J=8.4 Hz, 2H), 7.52 (d, J=0.8 Hz, 2H), 7.50-7.38 (m, 4H),7.28-7.24 (m, 1H), 7.21-7.18 (m, 1H), 4.6-4.46 (m, 1H), 4.26-4.21 (m,2H), 3.76-3.70 (m, 2H), 3.61 (d, J=10.8 Hz, 2H), 3.16 (s, 2H), 2.99 (s,3H), 2.86 (s, 3H), 2.66-2.59 (s, 2H), 2.31-2.21 (m, 4H), 2.07-2.02 (m,2H), 1.15 (s, 3H).

Example 1b4-{8-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-benzoicacid

Step 1. A microwave vial was charged with4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzoic acid ethylester (1.00 g, 2.77 mmol), 4-(4-chloro-phenyl)-piperidin-4-ol (879 mg,4.15 mmol), tris(dibenzylideneacetone)dipalladium(0) (256 mg, 0.28mmol), cesium carbonate (1.81 g, 5.54 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (321 mg, 0.55 mmol) anddioxane (12 mL). The vessel was sealed, evacuated and refilled withargon three times before being purged with argon whilst being sonicatedfor 5 minutes. The reaction mixture was stirred at 110° C. for 18 hoursthen cooled to room temperature before being filtered through a pad ofCelite, eluting with ethyl acetate. The filtrate was concentrated invacuo before being purified by flash chromatography on silica elutingwith 0-4% MeOH in dichloromethane.4-{8-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-benzoicacid ethyl ester was obtained as a pale yellow solid (1.13 g, 83%). LCMS(Method 1) [M+H]⁺492.4, R_(T)=4.07 min. ¹H NMR (400 MHz, DMSO-d₆) δ10.14 (s, 1H), 8.35 (dd, J=6.0, 1.5 Hz, 1H), 7.92-7.86 (m, 2H),7.82-7.76 (m, 2H), 7.60-7.53 (m, 2H), 7.43-7.34 (m, 2H), 6.99-6.88 (m,2H), 5.21 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.12 (d, J=11.8 Hz, 2H), 3.22(t, J=11.4 Hz, 2H), 2.13 (td, J=12.9, 4.3 Hz, 2H), 1.76 (d, J=12.7 Hz,2H), 1.30 (t, J=7.1 Hz, 3H).

Step 2. A mixture of4-{8-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-benzoicacid ethyl ester (5.12 g, 10.41 mmol), 2M LiOH aqueous solution (10.41mL, 20.82 mmol), methanol (25 mL), THF (150 mL) and water (15 mL) wasstirred at 55° C. for 18 hours then at room temperature for 24 hours.The methanol and THF were removed in vacuo before the solution wasadjusted to pH 4 with 1M HCl. The resultant precipitate was collected byfiltration then washed with water, diethyl ether and acetonitrilesequentially. The solid was dried under reduced pressure giving thetarget compound Example 1b as a pale yellow solid (4.38 g, 91%). LCMS(Method 2) [M+H]⁺ 464.1/466.1, R_(T)=4.32 min. ¹H NMR (400 MHz, DMSO-d₆)δ 12.45 (s, 1H), 10.10 (s, 1H), 8.36 (dd, J=5.9, 1.6 Hz, 1H), 7.95-7.84(m, 2H), 7.78 (d, J=2.1 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.62-7.51 (m,2H), 7.44-7.35 (m, 2H), 6.99-6.88 (m, 2H), 5.22 (s, 1H), 4.12 (d, J=11.7Hz, 2H), 3.21 (dd, J=13.3, 10.9 Hz, 2H), 2.12 (dp, J=20.8, 9.0, 6.6 Hz,2H), 1.76 (d, J=12.8 Hz, 2H).

Example 1c General Methods for Preparation of Amides

[4-[[8-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]phenyl]-[3-(methylamino)azetidin-1-yl]methanone(Example 1-47 in Table I)

A solution of4-[[8-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]benzoicacid (25 mg, 0.054 mmol, 1.0 equiv), tert-butylazetidine-3-ylmethylcarbamate HCl (25 mg, 0.11 mmol, 2.0 equiv), HATU(30 mg, 0.08 mmol, 1.5 equiv) and N,N-diisopropylethylamine (47 μL, 0.27mmol, 5.0 equiv) in DMF (1.0 mL) was stirred at 50° C. overnight. Thereaction mixture was concentrated under vacuum. A solution of crudeproduct in dichloromethane (1 mL) was mixed with trifluoroacetic acid(60 μL, 0.8 mmol, 15 equiv) and stirred at room temperature for 72hours. The reaction was concentrated under vacuum and the crude productwas purified by Prep-HPLC (Column, Gemini C18 100×30 mm; mobile phase,CH₃CN:NH₄OH/H₂O (10 mmol/L)=5%-85%, 10 min; flow rate, 70 mL/min;Detector, UV 254 nm) to give 7.4 mg (26%) of[4-[[8-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]pheny]-[3-(methylamino)azetidin-1-yl]methanoneas an off white solid, Example 1-47. ¹H NMR (400 MHz, DMSO-d₆) δ 9.92(s, 1H), 8.33 (dd, J=5.8, 1.7 Hz, 1H), 7.81-7.70 (m, 2H), 7.63-7.52 (m,4H), 7.46-7.35 (m, 2H), 6.97-6.86 (m, 2H), 5.19 (s, 1H), 4.43 (s, 1H),4.16-4.08 (m, 3H), 3.98 (s, 1H), 3.71 (s, 1H), 3.54-3.43 (m, 1H),3.30-3.16 (m, 2H), 2.22 (s, 3H), 2.19-2.05 (m, 2H), 1.80-1.72 (m, 2H).LCMS (Method 5): Observed MW=532.3; Rt 4.0 min.

Example 1d4-{8-[4-(4-chloro-phenyl)-4-hydroxymethyl-piperidin-1-yl]-1,8a-dihydro-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino}-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide(Example 1-246 in Table I)

Step 1. To the solution of 2-(4-chlorophenyl)acetonitrile (20.1 g,132.59 mmol, 1.00 equiv) and tert-butyl N,N-bis(2-chloroethyl)carbamate(35.4 g, 146.19 mmol, 1.10 equiv) in anhydrous DMF (200 mL) was addedsodium hydride (27 g, 60% in mineral oil, 666.73 mmol, 3.00 equiv)portionwise at 0° C. under N₂ over 2 hr. The resulting solution wasstirred at 60° C. for 1.5 hr, and then stirred overnight at roomtemperature. The reaction was quenched by the careful addition of 250 mLof sat. aq. NH₄Cl. The resulting solution was extracted with 3×200 mL ofdichloromethane. The combined extracts were washed with 2×300 mL ofbrine, then dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified on a silica gel column withdichloromethane/petroleum ether (1:1). 30 g (71%) of tert-butyl4-(4-chlorophenyl)-4-cyanopiperidine-1-carboxylate was obtained as ayellow solid. TLC: Rf=0.15; ethyl acetate/petroleum ether=1/5.

Step 2. The solution of tert-butyl4-(4-chlorophenyl)-4-cyanopiperidine-1-carboxylate (1 g, 3.12 mmol, 1.00equiv) in anhydrous tetrahydrofuran (5 mL, 61.71 mmol) was placed in a100-mL round-bottom flask purged and maintained under an inertatmosphere of nitrogen, then diisobutyl aluminium hydride (1 M inhexane, 7.8 mL, 7.81 mmol) was added dropwise with cooling in anice/water bath. The resulting solution was stirred for 1.5 hr at ambienttemperature. The reaction mixture was poured into 100 mL water/ice. Theresulting solution was extracted with 200 mL of ethyl acetate. Theextracts were washed with 2×50 mL of 2M hydrogen chloride solution, then3×50 mL of sat. aq. sodium bicarbonate and 1×50 mL of brine. The mixturewas dried over anhydrous sodium sulfate and concentrated under vacuum togive 610 mg crude tert-butyl4-(4-chlorophenyl)-4-formylpiperidine-1-carboxylate as a yellow solid,which was used in the next step without further purification. TLC:R_(f)=0.15; ethyl acetate/petroleum ether=1/5.

Step 3. The solution of tert-butyl4-(4-chlorophenyl)-4-formylpiperidine-1-carboxylate (610 mg, 1.88 mmol,1.00 equiv) in methanol (5 mL, 123.49 mmol) was placed in a 100-mLround-bottom flask, then NaBH₄ (144 mg, 3.81 mmol, 2.00 equiv) was addedin ice/water bath. The resulting solution was stirred at roomtemperature overnight. The reaction was quenched by the addition ofthree drops of water. The resulting mixture was concentrated undervacuum. The residue was purified on a silica gel column with ethylacetate/petroleum ether (1:10) to give 320 mg (52%) of tert-butyl4-(4-chlorophenyl)-4-(hydroxymethyl) piperidine-1-carboxylate as a whitesolid. TLC: R_(f)=0.4; ethyl acetate/petroleum ether=1/1.

Step 4. The solution of tert-butyl 4-(4-chlorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (300 mg, 0.92 mmol, 1.00 equiv) in HCl/dioxane(1M, 10 mL) was stirred for 2 h at room temperature. The resultingmixture was concentrated under vacuum, and sat. aq. NaHCO₃ was added tothe residue to make pH>10. The resulting mixture was concentrated todryness under vacuum. The residue was purified on a silica gel columneluting with dichloromethane/methanol (10:1) to give 180 mg (86%) of[4-(4-chlorophenyl)piperidin-4-yl]methanol as a yellow solid. LCMS(method 3): RT=1.03 min, m/z=226.0 [M+H]+

Step 5. The solution of4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(242 mg, 0.55 mmol, 1.50 equiv) in 1,4-dioxane (20 mL) was placed in a100-mL round-bottom flask purged and maintained with an inert atmosphereof nitrogen, then [4-(4-chlorophenyl)piperidin-4-yl]methanol (160 mg,0.71 mmol, 1.00 equiv), Cs₂CO₃ (357 mg, 1.10 mmol, 2.00 equiv),Pd₂(dba)₃.CHCl₃ (314.6 mg, 0.30 mmol, 0.45 equiv), BINAP (377.7 mg, 0.61mmol, 0.90 equiv) was added. The resulting solution was stirred for 48hours at 100° C. in an oil bath. The solids were filtered off. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column eluting with dichloromethane/methanol (5:1) to give acrude product. The crude product was purified again by Prep-HPLC underthe following conditions Column, XBridge™ Prep C18 OBD Column, 5 um,19×150 mm; mobile phase, water with 10 mmol NH₄HCO₃ and MeCN (30.0% MeCNup to 45.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, downto 30.0% in 2 min); Detector, UV 254/220 nm to give 20.8 mg (5%) of4-([8-[4-(4-chlorophenyl)-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide,Example 1-246 as an off-white solid. LCMS (Method 3): RT=2.09 min,m/z=588.2 [M+H]⁺, ¹H NMR (300 MHz, DMSO-d₆, ppm): δ 9.87 (s, 1H),8.29-8.28 (m, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.38(d, J=8.8 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 6.29-8.28 (m, 1H), 6.27-6.26(m, 1H), 4.71 (t, J=5.6 Hz, 1H), 3.88-3.78 (m, 2H), 3.41 (d, J=5.6 Hz,2H), 3.30 (s, 3H), 3.06-2.92 (m, 2H), 2.90-2.78 (m, 4H), 2.26-2.18 (m,5H), 2.17-2.02 (m, 2H), 1.73-1.85 (m, 3H), 1.57-1.51 (m, 2H).

Example 1e4-{8-[4-(4-Chloro-phenyl)-4-(2-cyano-ethyl)-piperidin-1-yl]-1,8a-dihydro[1,2,4]triazolo[1,5-a]pyridine-2-ylamino}-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide(Example 1-247 in Table I)

Step 1. Into a 2-L 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed tert-butyl4-oxopiperidine-1-carboxylate (100 g, 501.89 mmol, 1.00 equiv), toluene(800 mL), ethyl 2-cyanoacetate (56.8 g, 502.15 mmol, 1.00 equiv), NH₄OAc(38.5 g, 1.00 equiv), acetic acid (80 mL). The resulting solution wasstirred for 3 h at 110° C. The reaction mixture was cooled to roomtemperature and concentrated under vacuum. The resulting solution wasdiluted with 300 mL of H₂O and extracted with 2×1 L of ethyl acetate andthe organic layers combined and dried over anhydrous sodium sulfate. Thesolids were filtered off, and the filtrate was concentrated undervacuum. The residue was purified on a silica gel column with ethylacetate/petroleum ether (1:10). 110 g (74%) of tert-butyl4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate wasobtained as a white solid. TLC: R_(f)=0.4; ethyl acetate/petroleumether=1/4.

Step 2. Into a 3-L 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed tert-butyl4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (100 g,339.74 mmol, 1.00 equiv), tetrahydrofuran (500 mL), CuI (19.4 g, 101.86mmol, 0.30 equiv). The bromo(4-chlorophenyl)magnesium (1M in THF, 1.02L, 3.00 equiv) was added dropwise at 0° C. The resulting solution wasstirred for 2 h at 0° C. The resulting mixture was warmed to roomtemperature and concentrated under vacuum. The residue was suspended in1 L of EtOAc and the solids were filtered off. The filtrate wasconcentrated under vacuum. The residue was purified on a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:15˜1:10). 100 g(72%) of tert-butyl4-(4-chlorophenyl)-4-(1-cyano-2-ethoxy-2-oxoethyl)piperidine-1-carboxylatewas obtained as a light yellow solid. TLC: R_(f)=0.3; ethylacetate/petroleum ether=1/4.

Step 3. Into a 3-L 3-necked round-bottom flask, was placed tert-butyl4-(4-chlorophenyl)-4-(1-cyano-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate(100 g, 245.76 mmol, 1.00 equiv), ethanol (500 mL), water (500 mL),potassium hydroxide (30 g, 534.71 mmol, 2.18 equiv). The resultingsolution was stirred for 20 h at room temperature. EtOH was removedunder vacuum. The resulting aqueous solution was extracted with 1×200 mLof ether, and the pH value of the aqueous phase was adjusted to 6 with6N hydrogen chloride solution at 0° C., and then concentrated to drynessunder vacuum. The resulting solid was suspended in 500 mL of a mixtureof dichloromethane/MeOH (5:1, v/v), and the solid was filtered off. Thefiltrate was concentrated under vacuum to give 76 g of crude2-[1-[(tert-butoxy)carbonyl]-4-(4-chlorophenyl)piperidin-4-yl]-2-cyanoaceticacid as a light yellow solid, which was used in next step withoutfurther purification. TLC: R_(f)=0.3; dichloromethane/methanol=5/1.

Step 4. Into a 2-L 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen, was placed2-[1-[(tert-butoxy)carbonyl]-4-(4-chlorophenyl)piperidin-4-yl]-2-cyanoaceticacid (76 g, 200.61 mmol, 1.00 equiv), acetonitrile (800 mL), Cu₂O (28 g,195.68 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at85° C. The reaction mixture was cooled to room temperature andconcentrated under vacuum. The residual solid was suspended in 500 mL ofEA and the solid was filtered off. The filtrate was concentrated undervacuum, and the residue was purified on a silica gel column eluting withethyl acetate/petroleum ether (1:10˜1:2) to yield 50 g (74%) oftert-butyl 4-(4-chlorophenyl)-4-(cyanomethyl)piperidine-1-carboxylate asa light yellow solid. TLC: R_(f)=0.3; ethyl acetate/petroleum ether=1/2.¹H NMR (300 MHz, DMSO-d₆, ppm): δ 7.42-7.38 (m, 2H), 7.34-7.30 (m, 2H),3.79-3.72 (m, 2H), 3.13-3.04 (m, 2H), 2.54 (s, 2H), 2.32-2.27 (m, 2H),1.91-1.82 (m, 2H), 1.45 (s, 9H).

Step 5. Into a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed tert-butyl4-(4-chlorophenyl)-4-(cyanomethyl)piperidine-1-carboxylate (5 g, 14.93mmol, 1.00 equiv) and anhydrous tetrahydrofuran (80 mL). DIBAL-Hsolution (1 M in hexane, 30 mL, 2.00 equiv) was added dropwise at 0° C.The resulting solution was stirred for 2 h at 0° C. The reaction wasthen quenched by addition of 40 mL of water/ice. The resulting solutionwas extracted with 2×200 mL of ethyl acetate. The organic layers werecombined, washed with 1×20 mL of 1 M hydrogen chloride and 1×20 mL ofsodium bicarbonate saturated solution, and dried over anhydrous sodiumsulfate. The solid was filtered off and the filtrate was concentratedunder vacuum to yield 3 g of crude tert-butyl4-(4-chlorophenyl)-4-(2-oxoethyl)piperidine-1-carboxylate as colorlessoil. TLC: R_(f)=0.4; ethyl acetate/petroleum ether=1/2.

Step 6. Into a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of tert-butyl4-(4-chlorophenyl)-4-(2-oxoethyl)piperidine-1-carboxylate (3 g, 8.88mmol, 1.00 equiv) in methanol (80 mL), NaBH₄ (680 mg, 17.89 mmol, 1.00equiv) was added portionwise. The resulting solution was stirred for 10min at 25° C. The reaction was then quenched by the addition of 5 mL ofwater. The resulting mixture was concentrated under vacuum. The residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1:2˜1:1) to yield 1.4 g (46%) of tert-butyl4-(4-chlorophenyl)-4-(2-hydroxyethyl)piperidine-1-carboxylate as a whitesolid. TLC: R_(f)=0.3; ethyl acetate/petroleum ether=1/1.

Step 7. To a mixture of tert-butyl4-(4-chlorophenyl)-4-(2-hydroxyethyl)piperidine-1-carboxylate (600.00mg, 1.77 mmol, 1.00 equiv) and DIPEA (930 mg, 7.06 mmol, 4.00 equiv) indry dichloromethane (20.00 mL, 314.60 mmol, 178.20 equiv) was added Ms₂O(630 mg, 3.53 mmol, 2.00 equiv) dropwise under N₂. The resultingsolution was stirred for 4 h at ambient temperature. The resultingmixture was concentrated under vacuum. The residue was purified on asilica gel column with ethyl acetate/petroleum ether (1/4) to give 550mg (67%) of tert-butyl4-(4-chlorophenyl)-4-[2-(methanesulfonyloxy)ethyl]piperidine-1-carboxylateas colorless oil. TLC: R_(f)=0.4; ethyl acetate/petroleum ether=1/2.

Step 8. A mixture of tert-butyl4-(4-chlorophenyl)-4-[2-(methanesulfonyloxy)ethyl]piperidine-1-carboxylate(550.00 mg, 1.32 mmol, 1.00 equiv) and NaCN (650 mg, 13.16 mmol, 10.00equiv) in DMSO (20.00 mL) was stirred overnight at 100° C. The reactionmixture was cooled, and diluted with 100 mL of ethyl acetate. Theresulting mixture was washed with 3×20 mL of H₂O. The organic phase wasdried over Na₂SO₄, and concentrated under vacuum. The residue waspurified on a silica gel column with ethyl acetate/petroleum ether(1:4). The collected fractions were combined and concentrated undervacuum to give 360 mg (71%) of tert-butyl4-(4-chlorophenyl)-4-(2-cyanoethyl) piperidine-1-carboxylate ascolorless oil. TLC: R_(f)=0.5; ethyl acetate/petroleum ether=1/2.

Step 9. A mixture of tert-butyl4-(4-chlorophenyl)-4-(2-cyanoethyl)piperidine-1-carboxylate (360 mg,1.03 mmol, 1.00 equiv) in 1M HCl/1,4-dioxane (30 mL) was stirred for 2 hat 25° C. The reaction mixture was concentrated under vacuum. Theresidue was dissolved in 5 mL of H₂O. The pH value of the solution wasadjusted to 8 with potassium carbonate. The resulting mixture wasconcentrated to dryness under vacuum. The residue was purified on asilica gel column with dichloromethane/methanol (5/1). The collectedfractions were combined and concentrated under vacuum. This resulted in180 mg of 3-[4-(4-chlorophenyl)piperidin-4-yl]propanenitrile as lightyellow oil. TLC: R_(f)=0.3; dichloromethane/methanol=5/1. LCMS (Method3): RT=1.05 min, m/z=249.0 [M+H]⁺;

Step 10. Into a 100-mL round-bottom flask purged and maintained under aninert atmosphere of nitrogen, was placed3-[4-(4-chlorophenyl)piperidin-4-yl]propanenitrile (180 mg, 0.72 mmol,1.00 equiv),4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(320 mg, 0.72 mmol, 1.00 equiv), 1,4-dioxane (20 mL, 335.12 mmol, 463.10equiv), Cs₂CO₃ (473 mg, 1.45 mmol, 2.00 equiv), XantPhos (84 mg, 0.15mmol, 0.20 equiv), Pd₂(dba)₃ (70 mg, 0.08 mmol, 0.10 equiv). Theresulting mixture was stirred for 20 h at 100° C. in an oil bath. Thereaction mixture was cooled and concentrated under vacuum. The residuewas applied onto a silica gel column eluting withdichloromethane/methanol (10:1 and 5:1). The obtained crude product (200mg) was purified again by Prep-HPLC with the following conditions(IntelFlash-1): Column, silica gel; mobile phase, CH₃CN/H₂O=20%increasing to CH₃CN/H₂O=60% within 17 min; Detector, UV 254 nm to give27.2 mg (6%) of4-([8-[4-(4-chlorophenyl)-4-(2-cyanoethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off-white solid. LCMS (Method 3): RT=1.78 min, m/z=611.1 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆, ppm): δ 9.88 (s, 1H), 8.30 (d, J=6.0 Hz, 1H),7.71 (d, J=8.8 Hz, 2H), 7.48-7.43 (m, 4H), 7.33-7.31 (d, J=8.4 Hz, 2H),6.86 (t, J=7.2 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 3.80-3.77 (m, 2H),3.32-3.30 (m, 1H), 3.08-3.03 (m, 2H), 2.83-2.81 (m, 5H), 2.33-2.30 (m,2H), 2.15-2.00 (m, 5H), 1.99-1.96 (m, 4H), 1.95-1.65 (m, 4H), 1.58-1.55(m, 2H).

Example 1f4-{8-[4-(3,3-Dimethyl-azetidine-1-carbonyl)-piperidin-1-yl]-1,8a-dihydro[1,2,4]triazolo[1,5a]pyridine-2-ylamino}-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide(Example 1-42 in Table I)

Step 1. The mixture of4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(150 mg, 0.338 mmol) piperidine-4-carboxylic acid ethyl ester (159.4 mg,1.01 mmol) X-phos (39 mg, 0.067 mmol) Pd₂(dba)₃ (47 mg, 0.067 mmol)Cs₂CO₃ (329 mg, 1.01 mmol) in t-BuOH (3 mL) was heated to 100° C. andstirred for 1 h on microwave. The mixture was evaporated and water wasadded, extracted with EtOAc three times, the combined organic layer waswashed with water and brine and dried (Na₂SO₄). The solvent wasconcentrated and the residue was purified by column(dichloromethane:MeOH=10:1) to give1-(2-{4-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-piperidin-4-carboxylicacid ethyl ester (40 mg, 22% yield).

Step 2. To a solution of1-(2-{4-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-piperidin-4-carboxylicacid ethyl ester (100 mg, 0.192 mmol) in dioxane (2 mL) was added 1MNaOH aq (0.2 mL) and the mixture was heated to 80° C. and stirred for 2h. The solvent was evaporated and EtOAc was added, the mixture wasextracted with 1M NaOH aq, the combined aqueous layer was adjusted topH7 with 4M HCl, extracted with dichloromethane three times, thecombined organic layer was washed with water and brine, dried (Na₂SO₄),and the solvent was evaporated in vacuo to give1-(2-{4-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-piperidin-4-carboxylicacid (70 mg, 98% of yield).

The mixture of1-(2-{4-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-piperidin-4-carboxylicacid (70 mg, 0.142 mmol) HATU (64.7 mg, 0.17 mmol) DIPEA (55 mg, 0.426mmol) in DMF was stirred for 10 min at r,t. then 3,3-dimethyl azetidine(49.5 mg, 0.284 mmol) was added and the mixture was stirred for 2 h atr,t. The reaction mixture was poured into water and extracted threetimes with dichloromethane, the combined organic layer was washed withwater and brine, dried (Na₂SO₄) the solvent was evaporated and theresidue was purified by preparative scale-TLC to give4-{8-[4-(3,3-dimethyl-azetidine-1-carbonyl)-piperidin-1-yl]-1,8a-dihydro[1,2,4]triazolo-[1,5a]pyridine-2-ylamino}-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide(30 mg, 38% yield).

¹H NMR (400 MHz, methanol-d₄) δ 8.15 (d, J=5.51 Hz, 1H), 7.74 (d, J=8.60Hz, 2H), 7.39 (d, J=8.38 Hz, 2H), 6.83-6.91 (m, 2H), 4.24 (d, J=12.13Hz, 2H), 3.96 (s, 2H), 3.66 (s, 2H), 3.47 (br. s., 2H), 2.97 (s, 4H),2.72-2.87 (m, 5H), 2.48-2.56 (m, 1H), 2.10-2.19 (m, 2H), 1.90-2.04 (m,4H), 1.82 (d, J=11.25 Hz, 2H), 1.24-1.41 (m, 8H).

Example 1g4-(8-Benzyloxy-1,8a-dihydro-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide(Example 1-249 in Table I)

Step 1. To a solution of 4-iodobenzoic acid ethyl ester (5.0 g, 18.1mmol) was added 1M NaOH aq (18.1 mL, 18.1 mmol) and the mixture washeated to 100° C. and stirred for 1.5 h. The solvent was evaporated, theresidue was adjusted to pH6, and the precipitated solid was filtered offand washed with water to give 4-iodobenzoic acid (4.0 g, 89% yield).

Step 2. To a mixture of 4-iodobenzoic acid (1.0 g, 4 mmol) HATU (1.8 g,4.8 mmol) in DMF was added DIPEA (1.5 g, 12 mmol) at 0° C. and themixture was stirred for 10 min, thenmethyl-(1-methyl-piperidin-4-yl)-amine (1.02 g, 8 mmol) was added, andthe reaction mixture was stirred for 2 h at r,t. The reaction mixturewas poured into water and the mixture was extracted with EtOAc threetimes. The combined organic layer was washed with water and brine, dried(Na₂SO₄), the solvent was evaporated in vacuo to give4-iodo-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (1.2 g, 83% ofyield).

Step 3. The mixture of 3-benzyloxy-pyridin-2-ylamine (400 mg, 2 mmol)EtOCONCS (282 uL) in dioxane was stirred overnight at rt the solvent wasevaporated and the residue (600 mg) was used for the next step withoutpurification.

Step 4. To a solution of NH₂OH—HCl (704 mg, 10.6 mmol) DIPEA (1 mL, 6.6mmol) in MeOH (4 mL) and EtOH (4 mL) was added a solution of thethiourea prepared in step 3 (600 mg, 2.12 mmol) in MeOH (4 mL) and EtOH(4 mL) at rt the mixture was stirred at r,t for 1 h and then at 60° C.for 2 h. The solvent was evaporated and saturated NaHCO₃ solution wasadded to the residue. The aqueous layer was extracted three times withdichloromethane, the combined organic layer was washed with water andbrine, dried (Na₂SO₄), the solvent was evaporated and solid was washedwith petroleum ether to give8-benzyloxy-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine (430 mg, 86% ofyield).

¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J=6.39 Hz, 1H), 7.42-7.50 (m, 2H),7.38 (t, J=7.39 Hz, 2H), 7.29-7.35 (m, 1H), 6.96 (d, J=7.72 Hz, 1H),6.73 (dd, J=6.84, 7.72 Hz, 1H), 5.89 (s, 2H), 5.25 (s, 2H).

Step 5. The mixture of8-benzyloxy-[1,2,4]triazolo[1,5-a]pyridine-2-ylamine (150 mg, 0.625mmol), 4-iodo-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (268.5 mg,0.75 mmol) Pd₂(dba)₃ (57 mg, 0.0625 mmol) Cs₂CO₃ (610 mg, 1.87 mmol)Xantphos (72 mg, 0.125 mmol) in dioxane was stirred for 2 h at 120° C.The solvent was concentrated, water was added and the mixture wasextracted three times with EtOAc. The combined organic layer was washedwith water and brine, dried (Na₂SO₄), the solvent was evaporated and theresidue was purified by prep TLC (dichloromethane:MeOH=7:1) to give4-(8-benzyloxy-1,8a-dihydro-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide(55 mg, 18% yield).

¹H NMR (400 MHz, methanol-d₄) δ 8.23 (d, J=6.39 Hz, 1H), 7.74 (d, J=8.60Hz, 2H), 7.53 (d, J=7.06 Hz, 2H), 7.29-7.43 (m, 5H), 7.09 (d, J=7.72 Hz,1H), 6.90-6.94 (m, 1H), 5.34 (s, 2H), 4.58 (s, 1H), 2.96 (s, 3H), 2.63(br. s., 7H), 2.07 (d, J=11.25 Hz, 2H), 1.93 (br. s., 2H)

Example 1hN-Methyl-N-(1-methyl-piperidin-4-yl)-4-(8-phenoxy-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-benzamide(Example 1-248 in Table I)

Step 1. To a solution of4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-benzoic acid (1 g,3.0 mmol), methyl-(1-methyl-piperidin-4-yl)-amine (460 mg, 3.6 mmol) andDIPEA (2.65 ml, 15 mmol) in DMSO (10.0 mL) was added HATU (1.37 g, 3.6mmol). The reaction mixture was stirred at 50° C. for 4 hours. Thereaction mixture was filtered, the filter cake was dried to give4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(1.1 g, 82.7%).

To a solution of4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(100 mg, 0.23 mmol) and phenol (84.6 mg, 0.9 mmol) in DMSO (5.0 mL) wasadded K₃PO₄ (287 mg, 1.35 mmol), picolinic acid (11.1 mg, 0.09 mmol) andCuI (8.6 mg, 0.05 mmol). The reaction mixture was stirred at 120° C.overnight. The reaction mixture was diluted with water (10 mL),extracted with EtOAc (3×10 mL), the combined organic layer wasconcentrated, then purified by preparative HPLC (YMC-Actus Triart C18150×30 mm×5 um column eluting with acetonitrile/water+0.05% NH₄OH) togiveN-methyl-N-(1-methyl-piperidin-4-yl)-4-(8-phenoxy-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)-benzamide(20.0 mg, 19.6%).

¹H NMR (400 MHz, methanol-d₄) δ 8.41 (d, J=6.17 Hz, 1H), 7.73 (d, J=8.38Hz, 2H), 7.43 (d, J=7.94 Hz, 2H), 7.38 (d, J=7.28 Hz, 2H), 7.21-7.25 (m,1H), 7.16 (d, J=7.94 Hz, 2H), 6.92-7.00 (m, 2H), 2.96 (s, 5H), 2.24-2.37(m, 3H), 1.93-2.01 (m, 2H), 1.73-1.83 (m, 2H), 1.31 (d, J=18.52 Hz, 3H).

LCMS (Method 4):R_(T)=0.740 min, m/z: 457.0 (M+H⁺).

Example 1i4-([8-[1-(1-cyanopropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide (Example 1-264 in Table I)

Step 1. A mixture of 2,3-dihydro-1,3-benzoxazol-2-one (3 g, 22.2 mmol)and phenyl[(trifluoromethane)sulfonyloxy]-lambda-3-iodanyltrifluoromethanesulfonate (11.6 g, 23.1 mmol) in in trifluoroacetic acid(50 mL) was heated under reflux for 30 min. The reaction mixture wasallowed to cool to room temperature and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting withDCM/EtOAc (2/1) to afford 1.6 g (48%) of5-hydroxy-2,3-dihydro-1,3-benzoxazol-2-one as an off-white solid.R_(f)=0.3, DCM/EtOAc=1/1.

Step 2. A mixture of 5-hydroxy-2,3-dihydro-1,3-benzoxazol-2-one (500 mg,3.31 mmol), (bromomethyl)benzene (570 mg, 3.33 mmol) and sodiumcarbonate (350 mg, 3.30 mmol) in N,N-dimethylformamide (10 mL) washeated at 40° C. for 3 h then allowed to cool to room temperature. ThepH of the reaction mixture was adjusted to ˜6 by the addition of 3 NHCl. EtOAc (100 mL) was added and the resulting mixture was washed withwater (3×30 mL) and brine (2×30 mL). The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with DCM/EtOAc(5/1) to afford 0.65 g (81%) of3-benzyl-5-hydroxy-2,3-dihydro-1,3-benzoxazol-2-one as a white solid.R_(f)=0.3, DCM/EtOAc=2/1.

Step 3. A microwave vial was charged with4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(220 mg, 0.50 mmol), CuI (9.45 mg, 0.05 mmol), Cs₂CO₃ (485 mg, 1.49mmol), 3-benzyl-5-hydroxy-2,3-dihydro-1,3-benzoxazol-2-one (120 mg, 0.50mmol), pyridine-2-carboxylic acid (12.2 mg, 0.10 mmol) and 1,4-dioxane(10 mL). The vessel was evacuated and refilled with nitrogen 3 times.The reaction mixture was heated at 120° C. for 3 h under microwaveirradiation. The reaction mixture was allowed to cool to roomtemperature and the precipitated solid was removed by filtration. Thefiltrate was concentrated under vacuum and the resultant residue waspurified by flash chromatography on silica gel eluting with DCM/MeOH(95/5) to afford 12.2 mg (4%) of4-([8-[(3-benzyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)oxy]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a white solid. ¹H NMR (300 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.69 (d,J=6.0 Hz, 1H), 7.69 (d, J=7.2 Hz, 2H), 7.37-7.16 (m, 9H), 7.08 (d, J=3.6Hz, 1H), 7.02-6.97 (m, 1H), 6.86-6.82 (m, 1H), 5.00 (s, 2H), 2.81-2.75(m, 5H), 2.50 (m, 1H), 2.12 (brs, 3H), 1.80 (m, 4H), 1.59 (m, 2H); LCMS(Method 7) R_(T)=1.79 min, m/z=604.2 [M+H]⁺.

Example 1j4-([8-[4-(4-chlorophenyl)-4-(1,2-dihydroxyethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide (Example 1-253 in Table I)

Step 1. A mixture of tert-butyl4-(4-chlorophenyl)-4-[2-(methanesulfonyloxy)-ethyl]piperidine-1-carboxylate(Example 1e, step 7, 1.1 g, 2.63 mmol) and t-BuOK (580 mg, 5.17 mmol) inTHF (50 mL) was heated under nitrogen at 60° C. for 4 h then cooled toroom temperature. The resulting mixture was concentrated under vacuumand the residue was purified by flash chromatography on silica geleluting with EtOAc/petroleum ether (1/4) to affordtert-butyl-4-(4-chlorophenyl)-4-ethenylpiperidine-1-carboxylate ascolourless oil (400 mg, 47%). TLC: R_(f)=0.5; EtOAc/petroleum ether=1/4.

Step 2. A mixture oftert-butyl-4-(4-chlorophenyl)-4-ethenylpiperidine-1-carboxylate (400 mg,1.24 mmol) and a solution of saturated HCl in 1,4-dioxane (10 mL) wasstirred for 1 h at room temperature then concentrated under vacuum. Theresidue was dissolved in H₂O (5 mL) and solid K₂CO₃ (2 g) was added. Theresulting mixture was concentrated under vacuum and the residue wastriturated with a mixture of DCM/MeOH (3/1(v/v), 40 mL). The remainingsolid was removed by filtration and the filtrate was concentrated undervacuum to afford 4-(4-chlorophenyl)-4-ethenylpiperidine as a yellow oil(200 mg). TLC: R_(f)=0.3; DCM/MeOH=5/1.

Step 3. A microwave vial was charged with4-(4-chlorophenyl)-4-ethenylpiperidine (130 mg, 0.59 mmol),4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(250 mg, 0.56 mmol), Pd₂(dba)₃.CHCl₃ (30 mg, 0.03 mmol), BINAP (36 mg,0.06 mmol), Cs₂CO₃ (390 mg, 1.20 mmol) and 1,4-dioxane (10 mL). Thesealed vial was evacuated and refilled with nitrogen 3 times. Theresulting mixture was heated at 100° C. for 20 h, allowed to cool toroom temperature and concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel eluting with a gradient of MeOH inDCM (1/10 to 1/3). Appropriate fractions were collected and evaporatedto afford 200 mg (58%) of4-([8-[4-(4-chlorophenyl)-4-ethenylpiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a yellow solid. LCMS (Method 11) R_(T)=1.65 min, m/z=584.2 [M+H]⁺.

Step 4: A mixture of4-([8-[4-(4-chlorophenyl)-4-ethenylpiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)-benzamide(200 mg, 0.34 mmol), 4-methylmorpholin-4-ium-4-olate (80 mg, 0.68 mmol)and osmium tetraoxide (174 mg, 0.68 mmol) in THF (30 mL) was stirred atroom temperature for 20 h. The reaction mixture was concentrated undervacuum and the residue was purified using a short pad of silica geleluting with DCM on a gradient of MeOH (1/20 to 1/3). Appropriatefractions were collected and evaporated and the residue was purified byFlash-Prep-HPLC using the following conditions: Column, silica gel;

mobile phase, MeCN/H₂O=15% increasing to MeCN/H₂O=50% over 20 min;Detection, UV 254 nm to afford 26.2 mg (12%) of4-([8-[4-(4-chlorophenyl)-4-(1,2-dihydroxyethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.88 (s, 1H), 8.28(d, J=6.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.47-7.30 (m, 6H), 6.82 (t,J=3.3 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 4.88 (d, J=4.8 Hz, 1H), 4.33 (t,J=2.7 Hz, 1H), 4.05-3.91 (m, 2H), 3.50-3.41 (m, 1H), 3.28-3.19 (m, 1H),2.91-2.64 (m, 8H), 2.46-2.30 (m, 3H), 2.21-2.03 (m, 5H), 1.93-1.69 (m,4H), 1.63-1.49 (m, 2H); LCMS (Method 7) R_(T)=2.01 min, m/z=618.2[M+H]⁺.

Example 1k4-([8-[4-(4-chlorophenyl)-4-(1-hydroxyethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-253 in Table I)

Methyl magnesium bromide (3 M in Et₂O, 0.28 mL, 0.9 mmol) was added to asolution of4-([8-[4-(4-chlorophenyl)-4-formylpiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(50 mg, 0.09 mmol) in THF (10 mL) at 0° C. The resulting solution wasstirred at 0° C. for 1 h then quenched by the addition of MeOH (2 mL).The resulting mixture was concentrated under vacuum and the residue waspurified using a short pad of silica gel eluting with MeOH/DCM (1/3).Appropriate fractions were combined and concentrated under vacuum andthe crude residue was purified by Flash-Prep-HPLC with the followingconditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile PhaseA:Water/10 mmol NH₄HCO₃, Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 30% B to 70% B over 10 min; Detection, UV 254 nm to afford13.1 mg (26%) of4-([8-[4-(4-chlorophenyl)-4-(1-hydroxyethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.84 (s, 1H), 8.27(d, J=6.3 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.46-7.37 (m, 4H), 7.32 (d,J=8.7 Hz, 2H), 6.83 (t, J=7.2 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 4.65 (d,J=4.8 Hz, 1H), 4.05-3.95 (m, 2H), 3.60 (t, J=5.7 Hz, 1H), 2.82-2.75 (m,5H), 2.73-2.63 (m, 4H), 2.28-2.26 (m, 1H), 2.12-1.85 (m, 5H), 1.85-1.75(m, 4H), 1.58-1.56 (m, 2H), 0.76 (d, J=6.3 Hz, 3H); LCMS (Method 10)R_(T)=1.64 min, m/z=602.2 [M+H]⁺.

Example 1l4-(8-(4-(4-chlorophenyl)-4-(2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-253 in Table I)

A mixture of trimethyl(trifluoromethyl)silane (242 mg, 1.70 mmol),4-([8-[4-(4-chlorophenyl)-4-formylpiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(100 mg, 0.17 mmol) and potassium carbonate (23 mg, 0.17 mmol) inN,N-dimethylformamide (10 mL) was heated under nitrogen at 80° C. for 5h. The reaction mixture was allowed to cool to room temperature andconcentrated under vacuum. The residue purified using a short pad ofsilica gel eluting with DCM/MeOH (3/1). Appropriate fractions werecollected and concentrated under vacuum and the crude residue waspurified by Flash-Prep-HPLC using the following conditions: Column,silica gel; mobile phase, MeCN/H₂O=15% increasing to MeCN/H₂O=50% over20 min; Detection, UV 254 nm to afford 13.1 mg (12%) of4-(8-(4-(4-chlorophenyl)-4-(2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.85 (s, 1H), 8.28(d, J=6.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 7.40(d, J=8.7 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H), 6.84 (t, J=7.2 Hz, 1H),6.72-6.66 (m, 2H), 4.10-4.04 (m, 3H), 2.87-2.76 (m, 5H), 2.75-2.62 (m,2H), 2.49-2.40 (m, 3H), 2.35-2.06 (m, 5H), 1.92-1.70 (m, 4H), 1.65-1.51(m, 2H); LCMS (Method 7) R_(T)=2.20 min, m/z=656.4 [M+H]⁺.

Example 1m Ethyl2-[4-(4-chlorophenyl)-1-[2-([4-[methyl(1-methylpiperidin-4-yl)carbamoyl]phenyl]amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]acetate(Example 1-254 in Table I)

Step 1. A mixture of tert-butyl4-(4-chlorophenyl)-4-(cyanomethyl)piperidine-1-carboxylate (2 g, 5.97mmol) and a solution of saturated HCl in 1,4-dioxane (30 mL) was stirredat room temperature overnight. The resulting mixture was concentratedunder vacuum, the residue dissolved in H₂O (20 mL) and the pH of thesolution was adjusted to 9 by the addition of solid potassium carbonate.The resulting mixture was concentrated under vacuum and the residue waspurified by flash chromatography on silica gel eluting with DCM/MeOH(3/1) to afford 1.3 g (93%) of2-[4-(4-chlorophenyl)piperidin-4-yl]acetonitrile as light yellow oil.TLC: R_(f)=0.2; DCM/MeOH=5/1.

Step 2. 2-[4-(4-chlorophenyl)piperidin-4-yl]acetonitrile (318 mg, 1.35mmol) and4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)-benzamide(500 mg, 1.13 mmol) were coupled following the procedure detailed inExample 1j, step 3. The reaction mixture was concentrated under vacuumand the residue was purified by flash chromatography on silica geleluting with DCM/MeOH (10/1) to afford 410 mg (61%) of4-([8-[4-(4-chlorophenyl)-4-(cyanomethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a light yellow solid. LCMS (Method 10) R_(T)=1.25 min, m/z=597.0[M+H]⁺.

Step 3. A mixture of4-([8-[4-(4-chlorophenyl)-4-(cyanomethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)-benzamide(400 mg, 0.67 mmol) in concentrated HCl (4 mL) and AcOH (1 mL) washeated at 100° C. for 20 h then allowed to cool to room temperature. Theresulting mixture was concentrated under vacuum to afford 450 mg of2-[4-(4-chlorophenyl)-1-[2-([4-[methyl(1-methylpiperidin-4-yl)carbamoyl]phenyl]amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]aceticacid; hydrochloride salt as yellow crude oil. TLC: R_(f)=0.3;DCM/MeOH=4/1.

Step 4. Thionyl chloride (4 mL, 55 mmol) was added dropwise to asolution of2-[4-(4-chlorophenyl)-1-[2-([4-[methyl(1-methylpiperidin-4-yl)carbamoyl]phenyl]amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]aceticacid (450 mg, 0.73 mmol) in ethanol (20 mL) at room temperature. Theresulting solution was heated at 80° C. for 3 h then allowed to cool toroom temperature. The resulting mixture was concentrated under vacuumand the resultant residue treated with saturated aqueous NaHCO₃ solution(4 mL). The resulting mixture was concentrated under vacuum and theresidue was purified using a short pad of silica gel eluting with DCM ona gradient of MeOH (1/10 to 1/5). Appropriate fractions were combinedand concentrated under vacuum and the crude residue was purified byPrep-HPLC with the following conditions: Column, XBridge Shield RP18 OBDColumn, 19*150 mm Sum 13 nm; mobile phase, Water with 10 mmol NH₄HCO₃and MeCN (12% MeCN up to 55% over 9 min); Detection, UV 254 nm to afford52.9 mg (11%) of ethyl2-[4-(4-chlorophenyl)-1-[2-([4-[methyl(1-methylpiperidin-4-yl)carbamoyl]phenyl]amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]acetateas an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 8.31(d, J=6.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.40(d, J=8.8 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 6.87 (t, J=7.2 Hz, 1H), 6.79(d, J=8.0 Hz, 1H), 3.83 (t, J=7.0 Hz, 2H), 3.79-3.68 (m, 2H), 3.27-3.22(m, 2H), 2.82-2.73 (m, 5H), 2.70-2.67 (m, 2H), 2.51-2.50 (m, 2H),2.37-2.33 (m, 2H), 2.20-2.12 (m, 5H), 1.86-1.79 (m, 3H), 1.65-1.56 (m,2H), 0.95 (t, J=7.5 Hz, 3H); LCMS (Method 7) R_(T)=2.88 min, m/z=644.3[M+H]⁺.

Example 1n4-([8-[4-(carbamoylmethyl)-4-(4-chlorophenyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-b]pyridazin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-298 in Table I)

A mixture of4-([8-[4-(4-chlorophenyl)-4-(cyanomethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)-benzamide(200 mg, 0.33 mmol), (E)-N-ethylidenehydroxylamine (110 mg, 1.67 mmol),PPh₃ (89 mg, 0.33 mmol) and Pd(OAc)₂ (38 mg, 0.17 mmol) in ethanol (20mL) was heated under nitrogen at 85° C. for 20 h. The reaction mixturewas allowed to cool to room temperature and concentrated under vacuum.The residue was purified using a short pad of silica gel eluting withDCM/MeOH (5/1). Appropriate fractions were combined and concentratedunder vacuum and the crude residue was purified by Flash-Prep-HPLC usingthe following conditions: Column, silica gel; mobile phase, MeCN/H₂O=15%increasing to MeCN/H₂O=55% over 13 min; Detection, UV 254 nm to afford55.3 mg (27%) of4-([8-[4-(carbamoylmethyl)-4-(4-chlorophenyl)piperidin-1-yl]-[1,2,4]-triazolo[1,5-b]pyridazin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)-benzamideas an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.85 (s, 1H), 8.29(d, J=6.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.38(d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.01 (s, 1H), 6.86 (t, J=7.2Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.58 (s, 1H), 3.75-3.72 (m, 2H),3.31-3.29 (m, 1H), 3.17-3.12 (m, 2H), 2.85-2.75 (m, 5H), 2.42-2.38 (m,2H), 2.33-2.19 (m, 5H), 2.12 (s, 3H), 1.79-1.56 (m, 5H); LCMS (Method 8)R_(T)=1.76 min, m/z=615.1 [M+H]⁺.

Example 1o4-([8-[4-(4-chlorophenyl)-4-[(dimethylcarbamoyl)methyl]piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-300 in Table I)

A mixture of crude2-[4-(4-chlorophenyl)-1-[2-([4-[methyl(1-methylpiperidin-4-yl)carbamoyl]phenyl]amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]aceticacid (200 mg), dimethylamine hydrochloride (132 mg, 1.62 mmol), DIPEA(260 mg, 2.01 mmol) and HATU (190 mg, 0.50 mmol) in DMF (10 mL) wasstirred at room temperature for 20 h. The reaction mixture wasconcentrated under vacuum and the residue was purified using a short padof silica gel eluting with DCM/MeOH (10/1). The filtrate wasconcentrated under vacuum and the crude product was purified byFlash-Prep-HPLC using the following conditions: Column, silica gel;mobile phase, MeCN/H₂O (containing NH₃.H₂O)=13% increasing to MeCN/H₂O(containing NH₃.H₂O)=45% over 13 min; Detection, UV 254 nm to afford19.9 mg of4-([8-[4-(4-chlorophenyl)-4-[(dimethylcarbamoyl)-methyl]piperidin-1-yl]-[1,2,4]triazolo-[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.85 (s, 1H), 8.29(d, J=6.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H), 7.38(d, J=8.7 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H), 6.86 (t, J=6.6 Hz, 1H), 6.77(d, J=8.4 Hz, 1H), 3.80-3.70 (m, 2H), 3.29-3.19 (m, 2H), 2.85-2.75 (m,4H), 2.69-2.51 (m, 8H), 2.49-2.37 (m, 3H), 2.36-2.23 (m, 3H), 2.20-2.10(m, 3H), 1.90-1.70 (m, 4H), 1.65-1.50 (m, 2H); LCMS (Method 7)R_(T)=2.15 min, m/z=643.3 [M+H]⁺.

Example 1p4-([8-[4-(4-chlorophenyl)-4-(2,2-difluoroethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-256 in Table I)

Step 1. DAST (0.5 mL, 2.87 mmol) was added dropwise to a solution oftert-butyl 4-(4-chlorophenyl)-4-(2-oxoethyl)piperidine-1-carboxylate(1.6 g, 4.74 mmol) in DCM (100 mL) at 0° C. The resulting solution wasstirred at 0° C. for 10 min then quenched by the addition of water (30mL). The resulting solution was extracted with DCM (2×100 mL) and thecombined organic layer was concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with EtOAc/hexane(1/10) to afford 500 mg (29%) of tert-butyl4-(4-chlorophenyl)-4-(2,2-difluoroethyl)piperidine-1-carboxylate aslight yellow oil. TLC: R_(f)=0.5; EtOAc/petroleum ether=1/4.

Step 2. A mixture oftert-butyl-4-(4-chlorophenyl)-4-(2,2-difluoroethyl)-piperidine-1-carboxylate(500 mg, 1.39 mmol) in saturated HCl solution of 1,4-dioxane (30 mL) wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated under vacuum, the residue dissolved in H₂O (5 mL) and solidK₂CO₃ (1 g) was added. The resulting mixture was concentrated undervacuum and the residue was triturated with DCM (100 mL). The remainingsolid was removed by filtration and the filtrate was concentrated undervacuum to afford 300 mg (crude) of4-(4-chlorophenyl)-4-(2,2-difluoroethyl)piperidine as a off white solid.LCMS (Method 7) R_(T)=1.16 min, m/z=260.1 [M+H]⁺.

Step 3.4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(300 mg, 0.68 mmol) and4-(4-chlorophenyl)-4-(2,2-difluoroethyl)piperidine (260 mg, 1.00 mmol)were coupled following the procedure detailed in Example 1j, step 3. Thereaction mixture was concentrated under vacuum and the residue waspurified by flash chromatography on silica eluting with DCM/MeOH (5/1).Appropriate fractions were combined and concentrated under vacuum. Thecrude product was purified by Flash-Prep-HPLC using the followingconditions: Column, silica gel; mobile phase, MeCN/H₂O=15% increasing toMeCN/H₂O=40% over 13 min; Detection, UV 254 nm to afford 38.8 mg (8%) of4-([8-[4-(4-chlorophenyl)-4-(2,2-difluoroethyl)piperidin-1-yl]-[1,2,4]triazolo-[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide;formic acid salt as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.85 (s, 1H), 8.30 (d, J=6.0 Hz, 1H), 8.19 (s, 1H), 7.71 (d, J=8.8 Hz,2H), 7.53 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.4 Hz,2H), 6.86 (t, J=7.2 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.82-5.53 (m, 1H),3.79-3.76 (m, 2H), 3.14-3.09 (m, 2H), 2.83-2.81 (m, 4H), 2.50-2.06 (m,10H), 1.91-1.57 (m, 6H); LCMS (Method 10) R_(T)=1.85 min, m/z=622.2[M+H]⁺.

Example 1q4-([8-[4-(4-chlorophenyl)-4-[(1E)-(methoxyimino)methyl]piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-250 in Table I)

A mixture of4-([8-[4-(4-chlorophenyl)-4-formylpiperidin-1-yl]-[1,2,4]triazolo[1,5a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(50 mg, 0.09 mmol), DIPEA (2 mL, 12.10 mmol) and N-methylhydroxylaminehydrochloride (630 mg, 7.54 mmol) in MeOH (10 mL) was stirred at roomtemperature for 20 h. The resulting mixture was concentrated undervacuum and the residue purified using a short pad of silica gel elutingwith DCM on a gradient of MeOH (1/5 to 1/3). Appropriate fractions werecombined and concentrated and the resultant residue was purified byFlash-Prep-HPLC using the following conditions: Column, silica gel;mobile phase, MeCN/H₂O=20% increasing to MeCN/H₂O=40% over 20 min;Detection, UV 254 nm to afford 3.2 mg (6%) of4-([8-[4-(4-chlorophenyl)-4-[(1E)-(methoxyimino)methyl]piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.07-8.06 (m, 1H),7.64 (d, J=8.8 Hz, 2H), 7.34-7.23 (m, 7H), 6.80-6.77 (d, J=6.4, 10.0 Hz,2H), 3.80-3.76 (m, 2H), 3.75 (s, 3H), 3.21-3.20 (m, 3H), 2.90-2.80 (m,5H), 2.30-1.95 (m, 8H), 1.90-1.75 (m, 3H), 1.65-1.55 (m, 2H); LCMS(Method 6) R_(T)=1.76 min, m/z=615.2 [M+H]⁺.

Example 1r4-([8-[4-(4-chlorophenyl)-4-(acetamidomethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-268 in Table I)

Step 1. Acetic anhydride (2.5 g, 24.49 mmol) was added to a solution oftert-butyl 4-(aminomethyl)-4-(4-chlorophenyl)piperidine-1-carboxylate(800 mg, 2.46 mmol) (prepared according to the procedure contained inJournal of Medicinal Chemistry, 2008, 51(7), 2147-2157) and DIPEA (3.2g, 24.8 mmol) in DCM (50 mL). On complete addition the reaction mixturewas stirred at room temperature for 20 h then concentrated under vacuum.The residue was purified by flash chromatography on silica gel elutingwith EtOAc/petroleum ether (1/4) to afford tert-butyl4-(4-chlorophenyl)-4-(acetamidomethyl)piperidine-1-carboxylate as anoff-white solid (900 mg, 99%). TLC: R_(f)=0.4; EtOAc/petroleumether=1/4.

Step 2. A mixture of tert-butyl4-(4-chlorophenyl)-4-(acetamidomethyl)piperidine-1-carboxylate (900 mg,2.45 mmol) in a saturated solution of HCl in 1,4-dioxane (20 mL) wasstirred at room temperature for 2 h. The resulting mixture wasconcentrated under vacuum and the residue was dissolved in H₂O (5 mL)and treated with solid K₂CO₃ (1 g). The resulting mixture wasconcentrated under vacuum and the residue triturated with a mixture ofDCM/MeOH (3/1(v/v), 50 mL). The remaining solid was removed byfiltration and the filtrate was evaporated to affordN-[[4-(4-chlorophenyl)piperidin-4-yl]methyl]acetamide as a white solid(400 mg). TLC: R_(f)=0.3; DCM/MeOH=5/1.

Step 3.4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(420 mg, 0.95 mmol) andN-[4-(4-chlorophenyl)piperidin-4-yl]methylacetamide (266 mg, 1.00 mmol)were coupled following the procedure detailed in Example 1j, step 3. Theresulting mixture was concentrated under vacuum and the residue waspurified using a short pad of silica gel eluting with DCM/MeOH (3/1).Appropriate fractions were combined and concentrated to afford crude4-([8-[4-(4-chlorophenyl)-4-(acetamidomethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a light-yellow solid (450 mg). A third of the above crude product(150 mg) was purified by Flash-Prep-HPLC using the following conditions:Column, silica gel; mobile phase, MeCN/H₂O=15% increasing toMeCN/H₂O=40% over 20 min; Detection, UV 254 nm to afford4-([8-[4-(4-chlorophenyl)-4-(acetamidomethyl)-piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methyl-piperidin-4-yl)benzamideas a off white solid (37.4 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.17 (d,J=6.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.40 (d,J=8.8 Hz, 4H), 6.88 (t, J=7.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 3.87-3.84(m, 2H), 3.43 (s, 2H), 3.12 (t, J=10 Hz, 2H), 3.03-3.00 (br, 2H), 2.98(s, 3H), 2.42-2.10 (m, 8H), 2.06-1.90 (m, 3H), 1.88 (s, 3H), 1.79 (br,2H); LCMS (Method 6) R_(T)=2.51 min, m/z=629.4 [M+H]⁺.

Example 1s4-([8-[4-(4-chlorophenyl)-4-(acetamidomethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide (Example 1-265 in Table I)

A solution of4-([8-[4-(4-chlorophenyl)-4-(acetamidomethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)-benzamide(200 mg, 0.32 mmol) in 12 N HCl aqueous solution (8 mL) and AcOH (2 mL)was heated at 100° C. for 20 h. The reaction mixture was allowed to coolto room temperature and concentrated under vacuum. DIPEA (1 mL) wasadded and the mixture was concentrated under vacuum. The residue waspurified by Prep-HPLC using the following conditions: Column, XBridgeShield RP18 OBD Column, 19*150 mm 5 um 13 nm; mobile phase, Water with10 mmol HCOOH and MeCN (10% MeCN to 55% over 9 min); Detection, UV 254nm to afford 4.1 mg of4-([8-[4-(aminomethyl)-4-(4-chlorophenyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]-pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide;formic acid salt as a light yellow solid. ¹H NMR (400 MHz, CD₃OD): δ8.60-8.50 (m, 1H), 8.19 (d, J=6.4 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H),7.56-7.52 (m, 4H), 7.42 (d, J=8.4 Hz, 2H), 6.90-6.85 (m, 2H), 3.95-3.85(m, 2H), 3.33-3.30 (m, 2H), 3.22 (s, 2H), 3.11-3.05 (m, 2H), 3.00 (s,3H), 2.90-2.35 (m, 7H), 2.30-1.80 (m, 7H); LCMS (Method 6): R_(T)=1.75min, m/z=587.2 [M+H]⁺.

Example 1t4-[(8-[4-[4-(difluoromethyl)phenyl]-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-267 in Table I)

Step 1. Sodium hydride (4.00 g, 166 mmol) was added portionwise to asolution of 2-(4-bromophenyl)acetonitrile (8 g, 40.8 mmol) andtert-butyl-N,N-bis(2-chloroethyl)carbamate (10.0 g, 41.3 mmol) in DMF(100 mL). On complete addition the resulting solution was stirred atroom temperature for 1 h and at 65° C. for an additional 2 h. Thereaction mixture was allowed to cool to room temperature, poured intocrushed ice (200 g) and extracted with DCM (3×500 mL). The combinedorganic layer was concentrated under vacuum and the residue was purifiedby flash chromatography on silica gel eluting with EtOAc/hexane (1/4) togive tert-butyl-4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate as anoff white solid (6.00 g, 40%). TLC: R_(f)=0.3; ethyl acetate/petroleumether=1/4.

Step 2. Into a 250-mL pressure tank reactor purged and maintained withan inert atmosphere of nitrogen, were placedtert-butyl-4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate (5 g, 13.69mmol), DIPEA (5 g, 38.69 mmol), Pd(dppf)Cl₂ (1.00 g, 1.37 mmol), DMSO(2.2 g, 28.16 mmol) and MeOH (150 mL) and the resulting solution washeated at 100° C. for 20 h under a pressure of 10 atm of CO. Thereaction mixture was allowed to cool to room temperature and the solventevaporated. The residue was purified by flash chromatography on silicagel eluting with EtOAc/petroleum ether (1/10 to 1/4) to affordtert-butyl-4-cyano-4-[4-(methoxycarbonyl)phenyl]piperidine-1-carboxylateas a off white solid (3.5 g, 74%). TLC: R_(f)=0.3; EtOAc/petroleumether=1/4.

Step 3. DIBAl-H (1 M in hexanes, 20 mL, 20 mmol) was added dropwise to asolution oftert-butyl-4-cyano-4-[4-(methoxycarbonyl)phenyl]piperidine-1-carboxylate(3.5 g, 10.2 mmol) and THF (100 mL) at 0° C. The resulting solution wasstirred at 0° C. for 0.5 h, quenched by the addition of water (3 mL) andconcentrated under vacuum. The resultant residue was purified by columnchromatography on silica eluting with petroleum ether on a gradient ofEtOAc (1/4 to 4/1). Appropriate fractions were combined and evaporatedto afford tert-butyl4-cyano-4-[4-(hydroxymethyl)-phenyl]piperidine-1-carboxylate as a whitesolid (3.00 g, 93%). TLC: R_(f)=0.3; EtOAc/petroleum ether=1/1.

Step 4. A mixture of tert-butyl4-cyano-4-[4-(hydroxymethyl)phenyl]piperidine-1-carboxylate (3.00 g,9.48 mmol), sodium bicarbonate (800 mg, 9.52 mmol) and DMP (4 g, 9.43mmol) in DCM (100 mL) was stirred at room temperature for 20 h. Theresulting mixture was evaporated and the resultant residue was purifiedby flash chromatography on silica gel eluting with EtOAc/petroleum ether(1/4). Appropriate fractions were combined and evaporated to affordtert-butyl-4-cyano-4-(4-formylphenyl)piperidine-1-carboxylate ascolourless oil (2.3 g, 77%). ¹H NMR (400 MHz, CDCl₃): δ 10.04 (s, 1H),7.94 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 4.48-4.19 (m, 2H),3.34-3.10 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.91 (m, 2H), 1.49 (s, 9H).

Step 5. DAST (2.0 mL, 12.4 mmol) was added to a solution of tert-butyl4-cyano-4-(4-formylphenyl)piperidine-1-carboxylate (2.50 g, 7.95 mmol)in DCM (100 mL) under nitrogen. The resulting solution was stirred atroom temperature for 20 h and quenched by the addition of saturatedaqueous NaHCO₃ solution (50 mL). The resulting solution was extractedwith DCM (3×100 mL) and the combined organic layer was dried over Na₂SO₄and concentrated. The residue was purified by flash chromatography onsilica gel eluting with EtOAc/hexane (1/10) to afford tert-butyl4-cyano-4-[4-(difluoromethyl)phenyl]piperidine-1-carboxylate ascolourless oil (1.20 g, 45%). TLC: R_(f)=0.3; EtOAc/petroleum ether=1/4.

Step 6. DIBAl-H (1 M in hexanes, 3 mL, 3 mmol) was added dropwise to asolution oftert-butyl-4-cyano-4-[4-(difluoromethyl)phenyl]piperidine-1-carboxylate(500 mg, 1.49 mmol) in diethyl ether (50 mL) under nitrogen at 0° C. Theresulting solution was stirred at 0° C. for 1 h then quenched by theaddition of water (1 mL). The precipitated solid was removed byfiltration and the filtrate was concentrated under vacuum to affordcrudetert-butyl-4-[4-(difluoromethyl)phenyl]-4-formylpiperidine-1-carboxylateas colourless oil (340 mg). The product was used in the next stepwithout purification. TLC: R_(f)=0.5; EtOAc/petroleum ether=1/4.

Step 7. NaBH₄ (38 mg, 1.00 mmol) was added to a solution of crudetert-butyl-4-[4-(difluoromethyl)phenyl]-4-formylpiperidine-1-carboxylate(340 mg, 1.00 mmol) in MeOH (10 mL). The resulting solution was stirredat room temperature for 10 min then quenched by the addition of water (2mL). The reaction mixture was concentrated under vacuum and theresultant residue was purified by flash chromatography on silica geleluting with hexane on a gradient of EtOAc (1/4 to 4/1). Appropriatefractions were collected and evaporated to affordtert-butyl-4-[4-(difluoromethyl)phenyl]-4-(hydroxymethyl)piperidine-1-carboxylateas colourless oil (150 mg, 44%). TLC: R_(f)=0.3; EtOAc/petroleumether=1/2.

Step 8. A mixture of tert-butyl4-[4-(difluoromethyl)phenyl]-4-(hydroxymethyl)piperidine-1-carboxylate(150 mg, 0.44 mmol) in a saturated solution of HCl in 1,4-dioxane (10mL) was stirred at room temperature for 2 h. The resulting mixture wasconcentrated under vacuum to afford crude[4-[4-(difluoromethyl)phenyl]piperidin-4-yl]methanol as a light yellowsolid (90 mg) as the hydrochloride salt. TLC: R_(f)=0.4; DCM/MeOH=5/1.

Step 9.4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide;hydrochloride salt (200 mg, 0.45 mmol) and4-[4-(difluoromethyl)phenyl]piperidin-4-ylmethanol (110 mg, 0.46 mmol)were coupled following the procedure detailed in Example 1j, step 3. Theresulting mixture was concentrated under vacuum and the residue waspurified using a short pad of silica gel eluting with DCM/MeOH (3/1).Appropriate fractions were combined and evaporated to afford a residuethat was purified by Flash-Prep-HPLC using the following conditions:Column, silica gel; mobile phase, MeCN/H₂O=15% increasing toMeCN/H₂O=40% over 20 min; Detection, UV 254 nm to afford4-[(8-[4-[4-(difluoromethyl)phenyl]-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1, 5-a]pyridin-2-yl)amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a off white solid (37 mg, 14%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s,1H), 8.29 (d, J=6.0 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.60-7.53 (m, 4H),7.32 (d, J=8.4 Hz, 2H), 7.16-6.83 (m, 2H), 6.75 (d, J=8.0 Hz, 1H), 4.74(t, J=5.4 Hz, 1H), 3.87-3.83 (m, 2H), 3.45 (d, J=5.6 Hz, 2H), 3.03-2.97(m, 2H), 2.88-2.72 (m, 5H), 2.31-2.21 (m, 2H), 2.16-2.05 (m, 5H),1.81-1.50 (m, 7H); LCMS (Method 10) R_(T)=1.52 min, m z=604.3 [M+H]⁺.

Example 1u4-([8-[4-(hydroxymethyl)-4-[4-(methylsulfanyl)phenyl]piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-251 in Table I)

Step 1. Sodium hydride (370 mg, 15.42 mmol) was added portionwise to amixture of 2-[4-(methylsulfanyl)phenyl]acetonitrile (500 mg, 3.06 mmol)and tert-butyl-N,N-bis(2-chloroethyl)carbamate (890 mg, 3.68 mmol) inN,N-dimethylformamide (20 mL) at 0° C. The resulting solution wasstirred for 10 min at 0° C. and then heated at 60° C. for 2 h. Thereaction mixture was allowed to cool to room temperature and poured ontosaturated aqueous ammonium chloride solution (50 mL). EtOAc (200 mL) wasadded and the phases were separated. The organic phase was washed withH₂O (3×50 mL), dried, filtered and the filtrate concentrated undervacuum. The resultant residue was purified by flash chromatography onsilica gel eluting with EtOAc/petroleum ether (1/5) to afford 570 mg(56%) of tert-butyl-4-cyano-4-[4-(methylsulfanyl)phenyl]piperidine-1-carboxylate as a light yellow solid. TLC:R_(f)=0.3; EtOAc/petroleum ether=1/4.

Step 2. DIBAl-H (1 M in hexanes, 3.4 mL, 3.4 mmol) was added dropwise toa solution oftert-butyl-4-cyano-4-[4-(methylsulfanyl)phenyl]piperidine-1-carboxylate(570 mg, 1.71 mmol) in diethyl ether (20 mL) at 0° C. The resultingsolution was stirred at 0° C. for 10 min and quenched by the addition ofwater (1 mL), citric (0.5 g) and celite (5 g). The precipitated solidwas removed by filtration. The filtrate was concentrated under vacuum toafford 300 mg of crudetert-butyl-4-formyl-4-[4-(methylsulfanyl)-phenyl]piperidine-1-carboxylateas a light yellow solid. TLC: R_(f)=0.2; EtOAc/petroleum ether=1/4.

Step 3. NaBH₄ (68 mg, 1.80 mmol) was added to a solution oftert-butyl-4-formyl-4-[4-(methylsulfanyl)phenyl]piperidine-1-carboxylate(300 mg, 0.89 mmol) in MeOH (10 mL). The resulting solution was stirredfor 30 min at room temperature then quenched by the addition of water (2mL). The resulting mixture was concentrated under vacuum and the residuepurified by flash chromatography on silica gel eluting with petroleumether on a gradient of EtOAc (1/4 to 1/1) to afford 150 mg (50%) oftert-butyl-4-(hydroxymethyl)-4-[4-(methylsulfanyl)phenyl]piperidine-1-carboxylateas light yellow oil.TLC: R_(f)=0.3; EtOAc/petroleum ether=1/1.

Step 4. A mixture oftert-butyl-4-(hydroxymethyl)-4-[4-(methylsulfanyl)-phenyl]piperidine-1-carboxylate(150 mg, 0.44 mmol) in a saturated solution of HCl in 1,4-dioxane (10mL) was stirred at room temperature for 2 h. The resulting mixture wasconcentrated under vacuum, H₂O (10 mL) was added and the pH of thesolution was adjusted to 9 by the addition of solid potassium carbonate.The resulting mixture was concentrated under vacuum and the residue wastriturated with a mixture of DCM/MeOH (5/1(v/v), 30 mL). The remainingsolid was removed by filtration and the filtrate was concentrated undervacuum to afford 200 mg (crude) of[4-[4-(methylsulfanyl)phenyl]piperidin-4-yl]methanol as a light yellowsolid. LCMS (Method 7) R_(T)=1.08 min, m/z=238.1 [M+H]⁺.

Step 5. 4-[4-(methylsulfanyl)-phenyl]piperidin-4-ylmethanol (170 mg,0.72 mmol) and4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(317 mg, 0.72 mmol) were coupled following the procedure detailed inExample 1j, step 3. The reaction mixture was concentrated and theresidue was purified using a short pad of silica gel eluting with DCM ona gradient of MeOH (1/10 to 1/2). The filtrate was concentrated undervacuum and the resultant residue was purified by Prep-HPLC using thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm5 um 13 nm; mobile phase, Water with 10 mmol NH₄HCO₃ and MeCN (15% MeCNup to 55% over 11 min); Detection, UV 254 nm to afford 31.8 mg (7%) of4-([8-[4-(hydroxymethyl)-4-[4-(methylsulfanyl)phenyl]piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.86 (s, 1H), 8.29(d, J=6.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.32(d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 6.85 (t, J=7.2 Hz, 1H), 6.74(d, J=7.6 Hz, 1H), 4.67 (t, J=5.4 Hz, 1H), 3.88-3.85 (m, 2H), 3.40-3.36(m, 2H), 2.96 (t, J=10.2 Hz, 2H), 2.86-2.72 (m, 5H), 2.46 (s, 3H),2.25-2.01 (m, 7H), 1.91-1.70 (m, 4H), 1.62-1.49 (m, 3H). LCMS (Method10) R_(T)=1.85 min, m/z=600.3 [M+H]⁺.

Example 1v4-([8-[4-(4-chlorophenyl)-4-(cyanomethyl)cyclohex-1-en-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide (Example 1-294 in Table I)

Step 1. A mixture of 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64.0 mmol),ethyl 2-cyanoacetate (7.24 g, 64.0 mmol), NH₄OAc (4.94 g, 64.1 mmol) andacetic acid (20 mL, 349 mmol) in toluene (200 mL) was heated undernitrogen at 110° C. for 3 h. The reaction mixture was allowed to cool toroom temperature and concentrated under vacuum, diluted with EtOAc (200mL), washed with H₂O (50 mL) and concentrated under vacuum. The residuewas purified by flash chromatography on silica gel eluting withpetroleum ether on a gradient of EtOAc (1/10 to 1/5) to afford 10 g(57%) of ethyl 2-cyano-2-[1,4-dioxaspiro[4.5]decan-8-ylidene]acetate asa white solid. TLC: R_(f)=0.4; EtOAc/petroleum ether=1/2.

Step 2. A solution of bromo(4-chlorophenyl)magnesium (1 M in THF, 12 mL,12 mmol) was added dropwise to a mixture of ethyl2-cyano-2-[1,4-dioxaspiro[4.5]decan-8-ylidene]acetate (1.00 g, 3.98mmol) and CuI (230 mg, 1.21 mmol) in THF (20 mL) under nitrogen at 0° C.The resulting solution was stirred for 2 h at 0° C., quenched by theaddition of 10 mL of ethanol and concentrated under vacuum. Theresultant residue was purified by flash chromatography on silica geleluting with petroleum ether on a gradient of EtOAc (1/10 to 1/5) toafford 1.2 g (70%) of ethyl2-[8-(4-chlorophenyl)-1,4-dioxaspiro-[4.5]decan-8-yl]-2-cyanoacetate aslight yellow oil. TLC: R_(f)=0.3; EtOAc/petroleum ether=1/2.

Step 3. A solution of KOH (1.2 g, 21.39 mmol) in water (10 mL) was addeddropwise to a solution of ethyl2-[8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl]-2-cyanoacetate (1.2g, 3.30 mmol) in ethanol (10 mL). On complete addition the mixture wasstirred at room temperature for 20 h then concentrated under vacuum. Theresultant residue was dissolved in H₂O (20 mL) and washed withdiethylether (2×50 mL). The pH of the aqueous phase was adjusted to 6 bythe addition of 6N HCl and the resulting mixture was concentrated undervacuum. The residue was triturated with DCM and the remaining solidremoved by filtration. The filtrate was concentrated under vacuum toafford 1 g of2-[8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl]-2-cyanoacetic acidas a light yellow solid. TLC: R_(f)=0.3; DCM/MeOH=5/1.

Step 4. A mixture of2-[8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl]-2-cyanoacetic acid(1 g, 2.98 mmol) and Cu₂O (480 mg, 3.35 mmol) in MeCN (30 mL) was heatedunder nitrogen at 85° C. for 2 h. The reaction mixture was allowed tocool to room temperature and concentrated under vacuum. The resultantresidue was purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (1/3) to afford 600 mg (62%) of2-[8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl]acetonitrile aslight yellow oil. TLC: R_(f)=0.3; EtOAc/petroleum ether=1/2.

Step 5. A mixture of2-[8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-yl]acetonitrile (600mg, 2.06 mmol) and PTSA (71 mg, 0.41 mmol) in propan-2-one (20 mL) andwater (5 mL) was heated at 80° C. for 20 h. The reaction mixture wasallowed to cool to room temperature and concentrated under vacuum. Water(20 mL) was added and the aqueous phase extracted with EtOAc (2×100 mL).The combined organic phase was evaporated and the resultant residuepurified by silica gel eluting with petroleum ether on a gradient ofEtOAc (1/5 to 1/2) to give 400 mg (72%) of2-[1-(4-chlorophenyl)-4-oxocyclohexyl]acetonitrile as a white solid.TLC: R_(f)=0.2; EtOAc/petroleum ether=1/2.

Step 6. A solution of n-BuLi (2.5 M in hexanes, 0.6 mL, 1.5 mmol) wasadded dropwise to a solution of diisopropylamine (190 mg, 1.88 mmol) inTHF (20 mL) under nitrogen at −70° C. The resulting solution was stirredat −70° C. for 0.5 h then a solution of2-[1-(4-chlorophenyl)-4-oxocyclohexyl]acetonitrile (300 mg, 1.21 mmol)in a minimum amount of THF was added. The resulting solution was stirredat −70° C. for 0.5 h before the addition of 1, 1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethane-sulfonamide(520 mg, 1.46 mmol). The resulting solution was stirred for 0.5 h at−70° C. then allowed to warm to room temperature. The reaction mixturewas concentrated under vacuum and the resultant residue purified byflash chromatography on silica gel eluting with petroleum ether on agradient of EtOAc (1/10 to 1/5) to afford 130 mg (20%) of4-(4-chlorophenyl)-4-(cyanomethyl)cyclohex-1-en-1-yltrifluoromethanesulfonate as light yellow oil. TLC: R_(f)=0.4;EtOAc/petroleum ether=1/2.

Step 7. A mixture of4-(4-chlorophenyl)-4-(cyanomethyl)cyclohex-1-en-1-yltrifluoromethanesulfonate (130 mg, 0.34 mmol), KOAc (100 mg, 1.02 mmol),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(105 mg, 0.41 mmol) and Pd(dppf)Cl₂ (57 mg, 0.08 mmol, 0.20 equiv) inDMSO (10 mL) was heated under nitrogen at 70° C. for 16 h. The reactionmixture was allowed to cool to room temperature, diluted with EtOAc (100mL) and washed with H₂O (3×20 mL). The organic phase was evaporated andthe resultant residue was purified by flash chromatography on silica geleluting with EtOAc/petroleum ether (1/10) to afford2-[1-(4-chlorophenyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]acetonitrile(100 mg, 49%) as light yellow oil. TLC: R_(f)=0.6; EtOAc/petroleumether=1/2.

Step 8. A mixture of2-[1-(4-chlorophenyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]acetonitrile(150 mg, 0.42 mmol),4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(190 mg, 0.43 mmol), K₃PO₄ (270 mg, 1.27 mmol) and Pd(PPh₃)₄ (100 mg,0.09 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was degassed andrefilled with nitrogen 3 times. The reaction mixture was heated at 100°C. for 20 h, allowed to cool to room temperature and concentrated undervacuum. The residue was purified using a short pad of silica gel elutingwith DCM/MeOH (10/1). Appropriate fractions were combined andconcentrated under vacuum. The resultant residue was purified byFlash-Prep-HPLC using the following conditions: Column, silica gel;mobile phase, MeCN/H₂O=13% increasing to MeCN/H₂O=45% over 11 min;Detection, UV 254 nm to afford 61.4 mg (24%) of4-([8-[4-(4-chlorophenyl)-4-(cyanomethyl)cyclohex-1-en-1-yl]-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.93 (s, 1H), 8.66 (d,J=5.7 Hz, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.44 (t,J=9.0 Hz, 4H), 7.33 (d, J=8.4 Hz, 2H), 6.98 (t, J=7.0 Hz, 1H), 3.29 (s,1H), 3.07-2.82 (m, 8H), 2.74-2.56 (m, 2H), 2.27-2.12 (m, 6H), 1.80 (s,4H), 1.59-1.56 (m, 2H); LCMS (Method 8) R_(T)=1.78 min, m/z=594.1[M+H]⁺.

Example 1w4-([8-[4-(hydroxymethyl)-4-[[(2,2,2-trifluoroethyl)amino]methyl]piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-266 in Table I)

Step 1. DIBAl-H (1 M in hexane, 30 mL, 30 mmol) was added dropwise to asolution oftert-butyl-4-[(benzyloxy)methyl]-4-cyanopiperidine-1-carboxylate (4 g,12.11 mmol) in diethyl ether (100 mL) under nitrogen at 0° C. Theresulting solution was stirred at 0° C. for 1 h then quenched by theaddition of water (2 mL). The precipitated solid was removed byfiltration and the filtrate was concentrated under vacuum. The resultantresidue was purified by chromatography on silica gel eluting withEtOAc/hexane (1/2) to affordtert-butyl-4-[(benzyloxy)methyl]-4-formylpiperidine-1-carboxylate asyellow oil (1.3 g, 32%). TLC: R_(f)=0.4; EtOAc/petroleum ether=1/2.

Step 2. A mixture oftert-butyl-4-[(benzyloxy)methyl]-4-formylpiperidine-1-carboxylate (1 g,3.00 mmol), 2,2,2-trifluoroethan-1-amine (1.5 g, 15.14 mmol), andtetrakis(propan-2-yloxy)titanium (850 mg, 2.99 mmol) in ethanol (30 mL)was heated under nitrogen at 60° C. for 2 h. AcOH (0.1 mL, 1.75 mmol)was added, followed by NaBH₃CN (370 mg, 5.89 mmol). The resultingsolution was heated at 60° C. for an additional 2 h then allowed to coolto room temperature. The mixture was concentrated under vacuum and theresultant residue was purified by flash chromatography on silica geleluting with EtOAc/hexane (1/10) to affordtert-butyl-4-[(benzyloxy)methyl]-4-[[(2,2,2-trifluoroethyl)amino]methyl]piperidine-1-carboxylateas colourless oil (310 mg, 25%). TLC: R_(f)=0.5; EtOAc/petroleumether=1/4.

Step 3. A mixture oftert-butyl-4-[(benzyloxy)methyl]-4-[[(2,2,2-trifluoroethyl)amino]methyl]piperidine-1-carboxylate(300 mg, 0.72 mmol) and 10% Pd/C (50 mg) in MeOH (20 mL) and aqueous 6 NHCl solution (1 mL) was stirred under H₂ at room temperature for 20 h.The catalyst was removed by filtration and the filtrate was concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with DCM/MeOH (1/3) to affordtert-butyl-4-(hydroxymethyl)-4-[[(2,2,2-trifluoroethyl)amino]methyl]piperidine-1-carboxylateas colourless oil (120 mg, 51%). LCMS (Method 12) R_(T)=0.66 min,m/z=327.0 [M+H]⁺.

Step 4. A solution oftert-butyl-4-(hydroxymethyl)-4-[[(2,2,2-trifluoroethyl)amino]-methyl]piperidine-1-carboxylate(120 mg, 0.37 mmol) in a saturated solution of HCl in 1,4-dioxane (6 mL)was stirred at room temperature for 1 h. The resulting mixture wasevaporated, H₂O (1 mL) was added, followed by solid K₂CO₃ (0.5 g). Theresulting mixture was concentrated under vacuum and the residue wastriturated with a mixture of DCM/MeOH (3/1(v/v), 30 mL) and theremaining solid was removed by filtration. The filtrate was concentratedunder vacuum to afford(4-[[(2,2,2-trifluoroethyl)-amino]methyl]piperidin-4-yl)methanol ascolourless oil (65 mg). TLC: R_(f)=0.2; DCM/MeOH=4/1.

Step 5. (4-[[(2,2,2-trifluoroethyl)amino]-methyl]piperidin-4-yl)methanol(55 mg, 0.24 mmol) and4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(100 mg, 0.23 mmol) were coupled following the procedure detailed inExample 1j, step 3. The reaction mixture was concentrated under vacuumand the residue purified using a short pad of silica gel eluting withDCM/MeOH (10/1). Appropriate fractions were combined and evaporated andthe resultant residue was purified by Flash-Prep-HPLC using thefollowing conditions: Column, silica gel; mobile phase, MeCN/H₂O=15%increasing to MeCN/H₂O=40% over 20 min; Detection, UV 254 nm to afford4-([8-[4-(hydroxymethyl)-4-[[(2,2,2-trifluoroethyl)amino]methyl]piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a off white solid (12.2 mg, 9%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.86(s, 1H), 8.31 (d, J=6.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4Hz, 2H), 6.88 (t, J=3.4 Hz, 1H), 6.82 (d, J=3.6 Hz, 1H), 4.61 (t, J=3.2Hz, 1H), 3.51-3.36 (m, 6H), 3.31-3.23 (m, 3H), 2.85-2.76 (m, 5H),2.70-2.65 (m, 2H), 2.33-2.24 (m, 1H), 2.18-2.04 (m, 3H), 1.91-1.70 (m,4H), 1.64-1.50 (m, 6H); LCMS (Method 7) R_(T)=1.21 min, m/z=589.4[M+H]⁺.

Example 1x4-([8-[4-(cyanomethyl)-4-cyclopentylpiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-257 in Table I)

Step 1. A solution of bromo(cyclopentyl)magnesium (1 M in THF, 20 mL,115.4 mmol) was added dropwise to a mixture oftert-butyl-4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate(Example 1e, step 2, 2 g, 6.79 mmol) and CuI (380 mg, 2.00 mmol) in THF(20 mL) under nitrogen at 0° C. The resulting solution was stirred 0° C.for 2 h at then quenched by the addition of ethanol (10 mL). The mixturewas concentrated under vacuum and the residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1/10)to afford 1.7 g (69%) oftert-butyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4-cyclopentylpiperidine-1-carboxylateas light yellow oil. TLC: R_(f)=0.4; EtOAc/petroleum ether=1/4.

Step 2. A mixture of potassium hydroxide (2.0 g, 35.65 mmol) andtert-butyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4-cyclopentylpiperidine-1-carboxylate(1.7 g, 4.66 mmol) in ethanol (20 mL) and water (20 mL) was stirred atroom temperature overnight. The reaction mixture was evaporated to halforiginal volume and washed with ether (3×30 mL). The pH of the aqueousphase was adjusted to 6 by the addition of 6N HCl aqueous solution andthe resulting mixture was concentrated under vacuum. The residue wastriturated with a mixture of DCM and MeOH (5/1(v/v), 50 mL) and theremaining solid was removed by filtration. The filtrate evaporated toafford 1.3 g (83%) of2-[1-[(tert-butoxy)carbonyl]-4-cyclopentylpiperidin-4-yl]-2-cyanoaceticacid as a light yellow solid. TLC: R_(f)=0.5; DCM/MeOH=5/1.

Step 3. A mixture of2-[1-[(tert-butoxy)carbonyl]-4-cyclopentylpiperidin-4-yl]-2-cyanoaceticacid (1.3 g, 3.86 mmol) and Cu₂O (550 mg, 3.84 mmol) in MeCN (30 mL) washeated at 85° C. for 2 h under nitrogen then allowed to cool to roomtemperature. The reaction mixture was concentrated under vacuum and theresidue purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (1/4) to afford 830 mg (73%) oftert-butyl-4-(cyanomethyl)-4-cyclopentylpiperidine-1-carboxylate ascolourless oil. TLC: R_(f)=0.4; EtOAc/petroleum ether=1/2.

Step 4. A mixture oftert-butyl-4-(cyanomethyl)-4-cyclopentylpiperidine-1-carboxylate (830mg, 2.84 mmol) in saturated HCl in 1,4-dioxane (30 mL) was stirred atroom temperature for 2 h. The resulting mixture was concentrated undervacuum and the residue was dissolved in H₂O (10 mL). The pH of theaqueous phase was adjusted to 9 by the addition of solid potassiumcarbonate. The resultant mixture was concentrated under vacuum and theresidue triturated with a mixture of DCM and MeOH (5/1(v/v), 10 mL). Theprecipitated solid was removed by filtration and the filtrate evaporatedto afford 580 mg (crude) of 2-(4-cyclopentylpiperidin-4-yl)acetonitrileas light yellow oil. TLC: R_(f)=0.3; DCM/MeOH=5/1.

Step 5.4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(200 mg, 0.45 mmol) and 2-(4-cyclopentylpiperidin-4-yl)acetonitrile (173mg, 0.90 mmol) were coupled following the procedure detailed in Example1j, step 3. The resulting mixture was concentrated under vacuum and theresidue purified using a short pad of silica gel eluting with DCM/MeOH(10/1). Appropriate fractions were combined and concentrated undervacuum and the crude product was purified by Prep-HPLC using thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 19*150 mmSum 13 nm; mobile phase, Water with 10 mmol NH₄HCO₃ and MeCN (13% MeCNup to 55% over 12 min); Detection, UV 254 nm to afford 55.6 mg (22%) of4-([8-[4-(cyanomethyl)-4-cyclopentylpiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆,): δ 9.85 (s, 1H), 8.34 (t,J=3.1 Hz, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H), 6.93-6.84(m, 2H), 3.84-3.82 (m, 2H), 3.18 (t, J=10.2 Hz, 2H), 2.82-2.73 (m, 7H),2.12 (s, 4H), 1.90-1.35 (m, 19H); LCMS (Method 10) R_(T)=1.69 min,m/z=555.3 [M+H]⁺.

Example 1yN-methyl-N-[1-(2-methylpropyl)piperidin-4-yl]-2-[4-([8-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetamide(Example 1-297 in Table I)

Step 1. A mixture of tert-butyl4-[2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate(13 g, 41.22 mmol) in a saturated solution of HCl in 1,4-dioxane (150mL) was stirred at room temperature overnight. The precipitated solidwas collected by filtration to afford 10 g of (crude) of thehydrochloride salt of8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amineas a yellow solid. LCMS (Method 7) R_(T)=0.49 min, m/z=216.0 [M+H]⁺.

Step 2. A mixture of8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-aminehydrochloride (10 g, 39.73 mmol), DIPEA (14 g, 108.32 mmol),4,4,4-trifluorobutanoic acid (6 g, 42.23 mmol) and HATU (16 g, 42.08mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperatureovernight. The reaction mixture was evaporated; water (250 mL) and EtOAc(200 mL) were added. The phases were separated, and the aqueous phasewas extracted with EtOAc (200 mL). The combined organic phase was washedwith brine, dried over sodium sulfate and concentrated under vacuum. Theresidue was purified by flash chromatography on silica gel eluting with65% EtOAc/petroleum ether. Appropriate fractions were combined andevaporated to afford 1-(4-[2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-1,2,3,6-tetrahydropyridin-1-yl)-4,4,4-trifluorobutan-1-one(10 g, 74%) as a yellow solid. LCMS (Method 8) R_(T)=1.18 min, m/z=340.0[M+H]⁺.

Step 3. tert-butyl nitrite (15.20 g, 147.4 mmol) was added to a solutionof1-(4-[2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-1,2,3,6-tetrahydropyridin-1-yl)-4,4,4-trifluorobutan-1-one(10.0 g, 29.5 mmol) and CuI (11.23 g, 59.0 mmol) in MeCN (150 mL) undernitrogen. The mixture was stirred for 20 min at room temperature thenheated at 55° C. for 30 min. The reaction mixture was allowed to cool toroom temperature and the precipitated solid removed by filtration. Thefiltrate was concentrated under vacuum and the residue was dissolved inwater (500 mL). The pH of the aqueous phase was adjusted to 7 by theaddition of 2M aqueous sodium hydroxide solution then extracted with DCM(3×200 mL). The combined organic layer was washed with brine (500 mL),dried over anhydrous sodium sulfate and concentrated. The residue waspurified by column chromatography eluting with DCM/EtOAc (3/1).Appropriate fractions were combined and evaporated to afford4,4,4-trifluoro-1-(4-[2-iodo-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-1,2,3,6-tetrahydropyridin-1-yl)butan-1-one(5.3 g, 40%) as a light yellow solid. LCMS (Method 7) R_(T)=1.48 min,m/z=450.9 [M+H]⁺.

Step 4. A degassed mixture oftert-butyl-2-(4-amino-1H-pyrazol-1-yl)acetate (796 mg, 4.04 mmol),Cs₂CO₃ (2.63 g, 8.07 mmol),4,4,4-trifluoro-1-(4-2-iodo-[1,2,4]triazolo[1,5-a]pyridin-8-yl-1,2,3,6-tetrahydropyridin-1-yl)butan-1-one(2 g, 4.44 mmol), Pd₂(dba)₃.CHCl₃ (418 mg, 0.40 mmol) and XantPhos (468mg, 0.81 mmol) in 1,4-dioxane (100 mL) was heated at 100° C. overnight.The reaction mixture was allowed to cool to room temperature and theprecipitated solid was removed by filtration. The filtrate wasconcentrated under vacuum and the residue purified by flashchromatography on silica gel eluting with 70% EtOAc/petroleum ether toafford 1.2 g (57%) of tert-butyl2-[4-([8-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetateas a yellow solid. LCMS (Method 7) R_(T)=1.46 min, m/z=520.0 [M+H]⁺.

Step 5. A mixture oftert-butyl-2-[4-([8-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetate(1.2 g, 2.31 mmol) in DCM (15 mL) and TFA (20 mL) was stirred at roomtemperature overnight. The resulting mixture was concentrated undervacuum to afford2-[4-([8-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetic acid (900 mg, 84%) as ayellow solid.

Step 6. A mixture of2-[4-([8-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]aceticacid hydrochloride (200 mg, 0.40 mmol), DIPEA (104 mg, 0.80 mmol),N-methyl-1-(2-methylpropyl)piperidin-4-amine (88 mg, 0.52 mmol) and HATU(198 mg, 0.52 mmol) in DMF (5 mL) was stirred at room temperature for 3h. The mixture was concentrated under vacuum and the residue dilutedwith water (60 mL). The aqueous phase was extracted with DCM (3×50 mL)and the combined organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica eluting with DCM/MeOH (20/1).The crude product was purified by Prep-HPLC using the followingconditions: Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobilephase, water with 10 mmol NH₃.H₂O and MeCN (40% MeCN up to 55% over 10min, up to 95% over 1 min, hold 95.0% for 1 min, down to 40% over 2min); Detection, UV 254/220 nm to afford 94.3 mg (38%) ofN-methyl-N-[1-(2-methylpropyl)piperidin-4-yl]-2-[4-([8-[1-(4,4,4-trifluorobutanoyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetamideas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.31 (s, 1H), 8.59-8.58(m, 1H), 7.80-7.77 (m, 1H), 7.48-7.37 (m, 3H), 6.99-6.95 (m, 1H),5.11-5.04 (m, 2H), 4.33-4.24 (m, 3H), 3.76-3.62 (m, 2H), 2.86-2.52 (m,11H), 2.01-1.43 (m, 9H), 0.89-0.77 (m, 6H); LCMS (Method 7) R_(T)=1.10min, m/z=616.3 [M+H]⁺.

Example 1z Methyl3-(4-[2-[4-([8-[4-(4-chlorophenyl)-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetyl]piperazin-1-yl)propanoate(Example 1-290 in Table I)

Step 1. A microwave vial was charged with1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-amine (630 mg, 2.95mmol), 8-bromo-2-iodo-[1,2,4]triazolo[1,5-a]pyridine (960 mg, 2.96mmol), Pd₂(dba)₃ (150 mg, 0.16 mmol), XantPhos (170 mg, 0.29 mmol),Cs₂CO₃ (1.9 g, 5.83 mmol) and 1,4-dioxane (15 mL). The vessel wasevacuated and refilled with nitrogen 3 times. The reaction mixture washeated at 60° C. for 20 h then allowed to cool to room temperature. Theresulting mixture was concentrated under vacuum and the residue waspurified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (1/1) to afford 800 mg (66%) ofN-[8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-amineas a red solid. TLC: R_(f)=0.5; EtOAc/petroleum ether=1/1.

Step 2.N-[8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-pyrazol-4-amine(400 mg, 0.98 mmol) and [4-(4-chlorophenyl)piperidin-4-yl]methanol (270mg, 1.20 mmol) were coupled following the procedure detailed in Example1j, step 3. The reaction mixture was concentrated under vacuum and theresidue was purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (1:1) to give 350 mg (65%) of[4-(4-chlorophenyl)-1-[2-[(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl)amino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]methanolas a yellow solid. LCMS (Method 12) R_(T)=1.12 min, m/z=554.2 [M+H]⁺.

Step 3. A mixture of[4-(4-chlorophenyl)-1-[2-[(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-4-yl)amino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]methanol(650 mg, 1.17 mmol) in a saturated solution of HCl in 1,4-dioxane (20mL) was stirred at room temperature for 20 h. The mixture wasconcentrated under vacuum to afford 500 mg of[4-(4-chlorophenyl)-1-[2-[(1H-pyrazol-4-yl)amino]-[1,2,4]triazolo[1,5-a]pyridine-8-yl]piperidin-4-yl]methanolas a light yellow solid. LCMS (Method 12) R_(T)=0.61 min, m/z=424.0[M+H]⁺.

Step 4. A mixture of[4-(4-chlorophenyl)-1-[2-[(1H-pyrazol-4-yl)amino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidin-4-yl]methanol(400 mg, 0.94 mmol), Cs₂CO₃ (1.00 g, 3.07 mmol) andtert-butyl-2-bromoacetate (190 mg, 0.97 mmol) in N,N-dimethylformamide(20 mL) was stirred at room temperature for 2 h. The reaction mixturewas diluted with EtOAc (100 mL) and washed with H₂O (3×30 mL). Theorganic phase was concentrated under vacuum and the residue was purifiedby flash chromatography on silica gel eluting with EtOAc to afford 500mg (98%) oftert-butyl-2-[4-([8-[4-(4-chlorophenyl)-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetateas yellow oil. LCMS (Method 12) R_(T)=0.98 min, m/z=538.3 [M+H]⁺.

Step 5. A mixture oftert-butyl-2-[4-([8-[4-(4-chlorophenyl)-4-(hydroxymethyl)-piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetate(500 mg, 0.93 mmol) in a saturated solution of HCl in 1,4-dioxane (20mL) was stirred at room temperature for 20 h then concentrated undervacuum to afford 400 mg of2-[4-([8-[4-(4-chlorophenyl)-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]aceticacid as a light yellow crude solid. LCMS (Method 12) R_(T)=0.44 min,m/z=482.0 [M+H]⁺.

Step 6. A mixture of2-[4-([8-[4-(4-chlorophenyl)-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]aceticacid (100 mg, 0.207 mmol), HATU (95 mg, 0.250 mmol), DIPEA (108 mg,0.836 mmol) and methyl 3-(piperazin-1-yl)propanoate (72 mg, 0.418 mmol)in N,N-dimethylformamide (10 mL) was stirred at room temperatureovernight then concentrated under vacuum. The residue was purified usinga short pad of silica gel eluting with DCM on a gradient of MeOH (1/10to 1/4). Appropriate fractions were combined and evaporated and thecrude product was purified by Prep-HPLC using the following conditions:Column, XBridge Shield RP18 OBD Column, 19*150 mm Sum 13 nm; mobilephase, Water with 10 mmol HCOOH and MeCN (10% MeCN up to 55% over 11min); Detection, UV 254 nm to afford 10.8 mg (8%) of methyl3-(4-[2-[4-([8-[4-(4-chlorophenyl)-4-(hydroxymethyl)piperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-1H-pyrazol-1-yl]acetyl]piperazin-1-yl)propanoate;formic acid salt as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.21 (s, 1H), 8.26 (s, 1H), 8.17 (d, J=6.4 Hz, 1H), 7.72 (s, 1H),7.47-7.37 (m, 5H), 6.77 (t, J=7.2 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 5.06(s, 2H), 4.69 (s, 1H), 3.86-3.78 (m, 2H), 3.59 (s, 3H), 3.50-3.35 (m,8H), 3.05-2.91 (m, 2H), 2.61-2.57 (m, 2H), 2.44-2.32 (m, 4H), 2.25-2.14(m, 2H), 2.09-1.97 (m, 2H); LCMS (Method 6) R_(T)=2.59 min, m/z=636.4[M+H]⁺.

Example 1aa4-([8-[(3aR,5R,6aS)-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl]-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-292 in Table I)

Step 1.4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(200 mg, 0.45 mmol) and octahydrocyclopenta[c]pyrrol-5-01 (86 mg, 0.68mmol) were coupled following the procedure detailed in Example 1j, step3. The reaction mixture was concentrated and the residue was purified byflash chromatography on silica eluting with DCM on a gradient of MeOH(1/10 to 1/5).

Appropriate fractions were combined and concentrated under vacuum toafford 300 mg of4-[(8-[5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a light yellow solid. LCMS (Method 8) R_(T)=1.04 min, m/z=490.1[M+H]⁺.

Step 2. A mixture of4-[(8-[5-hydroxy-octahydrocyclopenta[c]pyrrol-2-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(280 mg, 0.57 mmol), 4-methylmorpholin-4-ium-4-olate (340 mg, 2.90 mmol)and rutheniumoylolate; tetrapropylazanium (200 mg, 0.57 mmol) in DCM (20mL) was stirred at room temperature for 0.5 h. The resulting mixture wasconcentrated under vacuum and the residue purified by flashchromatography on silica gel eluting with DCM on a gradient of MeOH(1/10 to 1/3) to afford 130 mg (47%) ofN-methyl-N-(1-methylpiperidin-4-yl)-4-[(8-[5-oxo-octahydrocyclopenta[c]pyrrol-2-yl]-[1,2,4]triazolo-[1,5-a]pyridin-2-yl)amino]benzamideas a light yellow solid. TLC: R_(f)=0.3; DCM/MeOH=5/1.

Step 3. Phenyl magnesium chloride (2 M solution in THF, 0.45 mL, 0.9mmol) was added dropwise to a solution ofN-methyl-N-(1-methylpiperidin-4-yl)-4-[(8-[5-oxo-octahydrocyclopenta[c]pyrrol-2-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino]benzamide(110 mg, 0.23 mmol) in THF (10 mL) under nitrogen at 0° C. On completeaddition, the reaction mixture was stirred at 0° C. for 0.5 h, quenchedby the addition of MeOH (2 mL) and concentrated under vacuum. Theresidue was purified using a short pad of silica gel eluting with DCM ona gradient of MeOH (1/10 to 1/2). Appropriate fractions were combinedand concentrated under vacuum. The crude product was purified byPrep-HPLC using the following conditions: Column, XBridge Shield RP18OBD Column, 19*150 mm Sum 13 nm; mobile phase, Water with 10 mmolNH₄HCO₃ and MeCN (12% MeCN up to 56% over 13 min); Detection, UV 254 nmto afford 4.4 mg (3%) of 4-([8-[(3aR,5R,6aS)-5-hydroxy-5-phenyl-octahydrocyclopenta[c]pyrrol-2-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas an off white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.76 (s, 1H), 8.20(d, J=6.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H),7.34-7.30 (m, 4H), 7.22 (t, J=7.2 Hz, 1H), 6.89-6.86 (m, 1H), 6.54 (d,J=7.6 Hz, 1H), 5.09 (s, 1H), 3.89-3.84 (m, 2H), 3.73-3.69 (m, 2H),3.01-2.89 (m, 2H), 2.88-2.72 (m, 5H), 2.35-2.24 (m, 3H), 2.15-2.08 (m,3H), 2.00-1.94 (m, 2H), 1.89-1.66 (m, 4H), 1.62-1.54 (m, 2H); LCMS(Method 8) R_(T)=2.22 min, m/z=566.1 [M+H]⁺.

Example 1ab4-(4-chlorophenyl)-1-[2-([4-[methyl(1-methylpiperidin-4-yl)carbamoyl]phenyl]amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidine-4-carboxylicacid (Example 1-269 in Table I)

A mixture of4-([8-[4-(4-chlorophenyl)-4-cyanopiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(100 mg, 0.17 mmol) in 12 N aqueous HCl (4 mL) and acetic (1 mL) washeated at 100° C. for 8 h then allowed to cool to room temperature. Thereaction mixture was evaporated; MeOH (10 mL) and DIPEA (1 mL) wereadded. The resulting mixture was concentrated under vacuum and theresidue was purified by Prep-HPLC using the following conditions:Column, XBridge Shield RP18 OBD Column, 19*150 mm Sum 13 nm; mobilephase, Water with 10 mmol HCOOH and MeCN (10% MeCN up to 55% over 11min); Detection, UV 254 nm to afford4-(4-chlorophenyl)-1-[2-([4-[methyl(1-methylpiperidin-4-yl)carbamoyl]phenyl]amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]piperidine-4-carboxylicacid; formic acid salt as an off white solid (11.9 mg, 10%). ¹H NMR (400MHz, DMSO-d₆): δ 9.90 (s, 1H), 8.33 (t, J=3.6 Hz, 1H), 8.20 (s, 1H),7.73 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H),7.33 (d, J=8.4 Hz, 2H), 6.92-6.86 (m, 2H), 4.08-4.04 (m, 2H), 3.04 (t,J=11.2 Hz, 2H), 2.82 (s, 3H), 2.81 (br, 2H), 2.60-2.51 (m, 3H), 2.13 (s,3H), 2.00 (t, J=10.2 Hz, 2H), 1.91-1.70 (m, 4H), 1.60-1.57 (m, 2H); LCMS(Method 6) R_(T)=1.61 min, m/z=602.4 [M+H]⁺.

Example 1acN-methyl-4-([8-[4-methyl-4-(N-methylbenzenesulfonamido)cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-(1-methylpiperidin-4-yl)benzamide(Example 1-261 in Table I)

Step 1: Benzenesulfonyl chloride (329 mg, 1.86 mmol) was added dropwiseto a solution of tert-butyl-4-amino-4-methylpiperidine-1-carboxylate(400 mg, 1.87 mmol) and DIPEA (1 mL, 6.05 mmol) in DCM (50 mL) at roomtemperature. The resulting solution was stirred for 2 h thenconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with EtOAc/petroleum ether (1:5) toafford 540 mg (82%) oftert-butyl-4-benzene-sulfonamido-4-methylpiperidine-1-carboxylate as awhite solid. LCMS (Method 12) R_(T)=1.19 min, m/z=355.0 [M+H]⁺.

Step 1. A mixture of tert-butyl4-benzenesulfonamido-4-methylpiperidine-1-carboxylate (350 mg, 0.99mmol) and sodium hydride (80 mg, 3.33 mmol) in N,N-dimethylformamide (20mL) was stirred at room temperature for 20 min before addition ofiodomethane (560 mg, 3.95 mmol). The resulting solution was stirred for2 h at room temperature and then quenched by the addition of H₂O (50mL). The resulting solution was extracted with EtOAc (100 mL) and thelayers separated. The organic phase was dried over sodium sulfate andconcentrated under vacuum to afford 350 mg (96%) oftert-butyl-4-methyl-4-(N-methylbenzenesulfonamido)piperidine-1-carboxylateas a white solid. LCMS (Method 7) R_(T)=1.57 min, m/z=369.0 [M+H]⁺.

Step 2. Using similar boc deprotection conditions described for Example1r, step 2, N-methyl-N-(4-methylpiperidin-4-yl)benzenesulfonamidehydrochloride (230 mg, 79%) was prepared fromtert-butyl-4-methyl-4-(N-methylbenzene-sulfonamido)piperidine-1-carboxylate(350 mg). LCMS (Method 9) R_(T)=1.05 min, m/z=269.0 [M+H]⁺.

Step 3.4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(150 mg, 0.34 mmol) andN-methyl-N-(4-methylpiperidin-4-yl)benzenesulfonamide hydrochloride (150mg, 0.49 mmol) were coupled following the procedure detailed in Example1j, step 3. The reaction mixture was allowed to cool to room temperatureand the precipitated solid was removed by filtration. The filtrate wasconcentrated under vacuum and the residue was purified by flashchromatography on silica gel eluting with DCM/MeOH (100/6) to afford 85mg (40%) ofN-methyl-4-([8-[4-methyl-4-(N-methylbenzenesulfonamido)-cyclohexyl]-[1,2,4]triazolo-[1,5-a]pyridin-2-yl]amino)-N-(1-methylpiperidin-4-yl)benzamideas a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.85 (s, 1H), 8.33 (d,J=6.0 Hz, 1H), 7.87 (dd, J=1.2, 7.8, Hz, 1H), 7.72-7.57 (m, 5H), 7.33(d, J=8.7 Hz, 2H), 6.89 (t, J=7.2 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H),3.57-3.54 (m, 2H), 3.40-3.28 (m, 3H), 2.88 (s, 3H), 2.82-2.71 (m, 5H),2.28-2.49 (m, 2H), 2.11 (s, 3H), 1.97-1.70 (m, 6H), 1.62-1.51 (m, 2H),1.23 (s, 3H); LCMS (Method 11) R_(T)=1.59 min, m/z=631.2 [M+H]⁺.

Example 1ad4-[[8-(4-acetamido-4-methylpiperidin-1-yl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 1-260 in Table I)

Step 1. Acetyl chloride (350 mg, 4.46 mmol) was added dropwise to asolution of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (600 mg,2.80 mmol) and DIPEA (2 mL, 12.10 mmol) in DCM (50 mL). The reactionmixture was stirred at room temperature for 2 h then washed with H₂O (50mL). The organic layer was dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to afford 850 mg oftert-butyl-4-acetamido-4-methylpiperidine-1-carboxylate as brown oil.LCMS (Method 7) R_(T)=1.26 min, m/z=257.0 [M+H]⁺.

Step 2. Using the boc deprotection method described in Example 1r, step2, N-(4-methylpiperidin-4-yl)acetamide as a brown oil (350 mg) wasprepared from tert-butyl-4-acetamido-4-methylpiperidine-1-carboxylate(850 mg). LCMS (Method 6) R_(T)=0.69 min, m/z=157.0 [M+H]⁺.

Step 3.4-([8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(200 mg, 0.45 mmol) and N-(4-methylpiperidin-4-yl)acetamide (106 mg,0.68 mmol) were coupled following the procedure detailed in Example 1j,step 3. The reaction mixture was allowed to cool to room temperature andthe precipitated solid removed by filtration. The filtrate wasconcentrated under vacuum and the residue was purified by flashchromatography on silica gel eluting with DCM/MeOH (100/7) to afford 45mg (19%) of4-[[8-(4-acetamido-4-methylpiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzamide asa white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.85 (s, 1H), 8.32 (d, J=5.6Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.73 (s, 1H), 6.89 (t, J=7.2 Hz, 1H),6.83 (d, J=7.6 Hz, 1H), 3.78-3.75 (m, 2H), 3.33 (s, 1H), 3.12 (t, J=10.2Hz, 2H), 2.82-2.75 (m, 5H), 2.26 (d, J=13.6 Hz, 2H), 2.11 (s, 3H),1.83-1.72 (m, 6H), 1.57-1.56 (m, 4H), 1.34 (s, 3H); LCMS (Method 8)R_(T)=1.69 min, m/z=519.2 [M+H]⁺.

The immediately preceding Examples may be modified via conventionallyknown chemistries to provide access to other compounds that fall withinthe scope of the present invention, such as compounds of Formula 0,non-limiting examples of which are seen in Table I.

TABLE I

          Ex           R²

      LCMS (ESI) m/z [M + H⁺] 1-1

538 1-2

″ 546 1-3

″ 464 1-4

″ 522 1-5

″ 554 1-6

″ 478 1-7

″ 554 1-8

″ 478 1-9

″ 505 1-10

″ 491 1-11

″ 473 1-12

″ 448 1-13

″ 525 1-14

″ 536 1-15

″ 536 1-16

″ 542 1-17

″ 574 1-18

″ 574 1-19

″ 541 1-20

″ 541 1-21

″ 565 1-22

″ 565 1-23

″ 503 1-24

″ 505 1-25

″ 505 1-26

″ 594 1-27

″ 517 1-28

″ 519 1-29

″ 506 1-30

″ 581 1-31

″ 518 1-32

″ 519 1-33

″ 519 1-34

″ 560 1-35

″ 574 1-36

″ 568 1-37

″ 558 1-38

″ 582 1-39

″ 554 1-40

″ 570 1-41

″ 563 1-42

″ 559 1-43

″ 540 1-44

″ 629 1-45

″ 549 1-46

″ 496 1-47

532 1-48 ″

572 1-49 ″

588 1-50 ″

588 1-51 ″

644 1-52 ″

614 1-53 ″

586 1-54 ″

572 1-55 ″

572 1-56 ″

586 1-57 ″

568 1-58 ″

568 1-59 ″

572 1-60 ″

572 1-61 ″

588 1-62 ″

546 1-63 ″

568 1-64 ″

568 1-65 ″

588 1-66 ″

614 1-67 ″

626 1-68 ″

594 1-69 ″

590 1-70 ″

588 1-71 ″

617 1-72 ″

608 1-73 ″

666 1-74 ″

665 1-75 ″

572 1-76 ″

572 1-77 ″

618 1-78 ″

659 1-79 ″

651 1-80 ″

602 1-81 ″

586 1-82 ″

617 1-83 ″

608 1-84 ″

576 1-85 ″

582 1-86 ″

574 1-87 ″

560 1-88 ″

560 1-89 ″

572 1-90 ″

528 (M + H − H2O) 1-91 ″

604 1-92 ″

532 1-93 ″

604 1-94 ″

604 1-95 ″

590 1-96 ″

603 1-97 ″

589 1-98 ″

590 1-99 ″

588 1-100 ″

588 1-101 ″

576 1-102 ″

574 1-103 ″

574 1-104 ″

574 1-105 ″

560 1-106 ″

560 1-107 ″

548 1-108 ″

534 1-109 ″

582 1-110 ″

608 1-111 ″

568 1-112 ″

609 1-113 ″

639 (M + H − H2O) 1-114 ″

623 1-115 ″

582 1-116 ″

626 1-117 ″

629 1-118 ″

644 1-119 ″

645 1-120 ″

618 1-121 ″

622 1-122 ″

623 1-123 ″

623 1-124 ″

608 1-125 ″

616 1-126 ″

609 1-127 ″

602 1-128 ″

600 1-129 ″

602 1-130 ″

602 1-131 ″

588 1-132 ″

600 1-133 ″

590 1-134 ″

582 1-135 ″

582 1-136 ″

586 1-137 ″

586 1-138 ″

568 1-139 ″

603 1-140 ″

582 1-141 ″

574 1-142 ″

594 1-143 ″

616 1-144 ″

608 1-145 ″

622 1-146 ″

608 1-147 ″

594 1-148 ″

610 1-149 ″

608 1-150 ″

693 1-151 ″

652 1-152 ″

603 1-153 ″

679 1-154 ″

588 1-155 ″

608 1-156 ″

622 1-157 ″

608 1-158 ″

622 1-159 ″

582 1-160 ″

568 1-161 ″

568 1-162 ″

568 1-163 ″

603 1-164 ″

574 1-165 ″

629 1-166 ″

560 1-167 ″

585 1-168 ″

572 1-169 ″

618 1-170 ″

588 1-171 ″

636 1-172 ″

616 1-173 ″

574 1-174 ″

631 1-175 ″

506 1-176 ″

532 1-177 ″

532 1-178 ″

561 1-179 ″

546 1-180 ″

546 1-181 ″

546 1-182 ″

546 1-183 ″

560 1-184 ″

560 1-185 ″

560 1-186 ″

574 1-187 ″

575 1-188 ″

562 1-189 ″

518 1-190 ″

558 1-191 ″

532 1-192 ″

546 1-193 ″

560 1-194 ″

520 1-195 ″

546 1-196 ″

562 1-197 ″

558 1-198 ″

546 1-199 ″

572 1-200 ″

546 1-201 ″

572 1-202 ″

560 1-203 ″

544 1-204 ″

546 1-205 ″

558 1-206 ″

546 1-207 ″

572 1-208 ″

572 1-209 ″

572 1-210 ″

572 1-211 ″

586 1-212 ″

586 1-213 ″

586 1-214 ″

586 1-215 ″

600 1-216 ″

600 1-217 ″

600 1-218 ″

600 1-219 ″

600 1-220 ″

616 1-221 ″

602 1-222 ″

616 1-223 ″

600 1-224 ″

558 1-225 ″

602 1-226 ″

586 1-227 ″

586 1-228 ″

586 1-229 ″

602 1-230 ″

602 1-231 ″

602 1-232 ″

544 1-233 ″

586 1-234 ″

558 1-235 ″

558 1-236 ″

572 1-237 ″

544 1-238 ″

544 1-239 ″

574 1-240 ″

558 1-241 ″

558 1-242 ″

574 1-243 ″

574 1-244 ″

588 1-245 ″

630 1-246

589 1-247

″ 611 1-248

″ 457 1-249

″ 471 1-250

″ 615 1-251

″ 600 1-252

″ 602 1-253

″ 656 1-254

″ 644 1-255

″ 603 1-256

″ 623 1-257

″ 555 1-258

″ 603 1-259

″ 595 1-260

″ 519 1-261

″ 631 1-262

″ 573 1-263

″ 616 1-264

″ 604 1-265

″ 588 1-266

″ 589 1-267

″ 604 1-268

″ 630 1-269

″ 603 1-270

″ 619 1-271

657 1-272 ″

603 1-273 ″

617 1-274 ″

587 1-275 ″

587 1-276 ″

623 1-277 ″

619 1-278 ″

619 1-279 ″

609 1-280 ″

629 1-281 ″

659 1-282 ″

659 1-283 ″

547 1-284 ″

583 1-285 ″

619 1-286 ″

605 1-287 ″

597 1-288 ″

609 1-289 ″

649 1-290 ″

637 1-291 ″

579 1-292

566 1-293

″ 551 1-294

595 1-295

586 1-296

632 1-297

616 1-298

616 1-299

″ 630 1-300

″ 644 1-301

″ 617 1-302

″ 581 1-303

″ 617

Example 2a Tert-butyl4-(2-((4-(methyl(1-methylpiperidin-4-yl)carbamoyl)-phenyl)-amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Step 1. To a solution of4-((8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(2.5 g, 5.1 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.8, 6.12 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (360 mg, 0.5mmol) in dioxane (60 mL) was added saturated sodium carbonate (20 mL);then the reaction mixture was degassed and heated at 110° C. undernitrogen for 4 h. The reaction mixture was poured into water (50 mL) andthe mixture was extracted with ethyl acetate (150 mL×3). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andthe filtrate was evaporated. The residue was purified on silica gelcolumn (eluting with 2% to 5% methanol in dichloromethane) to givetert-butyl4-(2-((4-(methyl(1-methylpiperidin-4-yl)carbamoyl)phenyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2 g, 72%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) 9.92 (s, 1H), 8.68 (d,J=6.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 2H), 7.50 (d, J=7.5 Hz, 1H), 7.31 (d,J=8.2 Hz, 2H), 7.02 (t, J=7.1 Hz, 1H), 4.17-4.00 (m, 3H), 3.65-3.49 (m,2H), 3.14 (d, J=5.3 Hz, 2H), 2.79 (s, 5H), 2.61 (brs, 2H), 2.11 (brs,2H), 1.78 (d, J=8.6 Hz, 1H), 1.56 (d, J=10.4 Hz, 2H), 1.42 (s, 9H), MS(Method 4): m/z 546.1 [M+l]⁺.

Step 2. A mixture of tert-butyl4-(2-((4-(methyl(1-methylpiperidin-4-yl)carbamoyl)phenyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.7 g, 3.1 mmol) in methanolic hydrochloride solution (4 M, 10 mL) wasstirred at room temperature for 1.5 h. The solvent was evaporated toafford 2.3 g of the hydrochloride salt ofN-methyl-N-(1-methylpiperidin-4-yl)-4-((8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)benzamide;bis-hydrochloride salt. ¹H NMR (400 MHz, DMSO-d₆): 10.00 (s, 1H), 9.47(brs, 1H), 8.74 (d, J=6.6 Hz, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.59 (d,J=7.5 Hz, 1H), 7.46 (brs, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.07 (t, J=7.2Hz, 1H), 3.49-3.28 (m, 4H), 2.86-2.80 (m, 5H), 2.65 (brs, 2H), 2.21 (d,J=11.9 Hz, 2H), 1.89 (s, 5H), 1.81 (d, J=12.6 Hz, 2H); LCMS (Method 4)m/z 446.1 [M+H]⁺.

Step 3. |To a mixture ofN-methyl-N-(1-methylpiperidin-4-yl)-4-((8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)benzamide;bis-hydrochloride salt (100 mg, 0.224 mmol) and Et₃N (75 mg, 0.448 mmol)in dichloromethane (5 mL) was added dropwise cyclopropanecarbonylchloride (26 mg, 0.248 mmol) at 0° C. The reaction mixture was allowedto warm to room temperature and stirred 0.5 h. MeOH (1 ml) was added andthe reaction mixture was concentrated. The residue was purified byprep-HPLC to give the final compound (Example 2-409, Table II) (40 mg,36.4% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s, 1H), 8.72-8.71 (m,1H), 7.75 (d, J=8.4 Hz, 2H), 7.55 (d, J=7.2 Hz, 1H), 7.44-7.33 (m, 3H),7.06 (t, J=6.8 Hz, 1H), 4.52 (s, 1H), 4.24 (s, 2H), 3.95 (s, 2H), 3.75(s, 1H), 2.82-2.75 (m, 6H), 2.62 (s, 1H), 2.12-2.02 (m, 5H), 1.81 (d,J=7.2 Hz, 4H), 1.59 (d, J=8.8 Hz, 2H) 0.78-0.73 (m, 4H). LCMS (Method4): R_(T)=0.711 min, m/z: 514.1 (M+H⁺).

Example 2b4-{8-[1-(4,4,4-Trifluoro-butyryl)-1,2,3,6-tetrahydro-pyridin-4-yl]-[1,2,4]triazolo[1,5a]pyridin-2-ylamino}-benzoicacid

To a suspension of4-[8-(1,2,3,6-tetrahydro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoicacid trifluoroacetic acid salt (5.00 g, 11.15 mmol) in dichloromethane(80 mL) was added triethylamine (5.13 mL, 36.80 mmol) and the reactioncooled to 0° C. To the reaction mixture was added a solution of4,4,4-trifluoro-butyric acid (1.88 g, 11.71 mmol) in dichloromethane (20mL). The resultant reaction mixture was warmed to room temperature andstirred for 18 hours before the further addition of a solution of4,4,4-trifluoro-butyric acid (1.88 g, 11.71 mmol) in dichloromethane (5mL) and stirred for 5 hours at room temperature. The reaction wasquenched with water then diluted with a mixture ofdichloromethane/water/acetonitrile. The suspension was loaded onto aSCX-2 cartridge and eluted with a mixture ofdichloromethane/methanol/water/acetonitrile. The solution wasconcentrated in vacuo giving the title compound as a triethylamine salt.The salt was suspended in dioxane (160 mL) and water (40 mL) beforebeing treated with SCX-2 resin (50 g). The mixture was stirred for 20minutes before the suspension was filtered and the filtrate concentratedin vacuo. The resultant residue was taken up into 1M NaOH and washedwith ethyl acetate (×3) then diethyl ether. The yellow aqueous phase wasacidified with 1M HCl to pH 5, forming a precipitate. The precipitatewas collected by filtration and washed with water then diethyl etherbefore being dried under reduced pressure. This gave the title compoundas an off white solid (3.73 g, 73%). LCMS (Method 1) [M+H]⁺460.3,R_(T)=3.14 min. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1H), 8.75 (dd,J=6.5, 1.1 Hz, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.79 (dd, J=8.9, 2.3 Hz,2H), 7.55 (t, J=7.6 Hz, 1H), 7.44-7.35 (m, 1H), 7.08 (t, J=7.1 Hz, 1H),4.29 (dd, J=26.4, 3.5 Hz, 2H), 3.74 (dt, J=11.1, 5.7 Hz, 2H), 2.78-2.50(m, 6H).

Example 2c4-[2-(4-Carboxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid ethyl ester

To a suspension of4-[8-(1,2,3,6-tetrahydro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoicacid trifluoroacetic acid salt (10.00 g, 22.3 mmol) in dichloromethane(100 mL) was added N,N-diisopropylethylamine (19 mL, 111.5 mmol) and thereaction cooled to 0° C. To the reaction mixture was added a solution ofethyl chloroformate (2.4 g, 22.3 mmol) dropwise over 5 minutes. Theresultant mixture was stirred at 0° C. for 1 h then evaporated underreduced pressure. The resultant residue was quenched with water and theresultant solid collected by filtration. The solid was washed withwater, methanol and diethyl ether and left to air dry. The solid waspurified by flash column chromatography on silica eluting with tolueneon a gradient of acetic acid (10-20%). Appropriate fractions werecollected and evaporated to afford a solid. The solid was trituratedwith methanol then diethyl ether to afford a white solid (6.2 g, 68%).¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 10.17 (s, 1H), 8.73 (dd,J=6.5, 1.1 Hz, 1H), 7.92-7.87 (m, 2H), 7.81-7.76 (m, 2H), 7.54 (t,dd=7.4, 1.0 Hz, 1H), 7.34 (brs, 1H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 4.18(brs, 2H), 4.10 (dt, J=7.0, 7.0 Hz, 2H), 3.65 (t, J=5.6 Hz, 2H),2.68-2.62 (m, 2H), 1.23 (t, J=7.1 Hz, 3H).

General Method for Preparation of Amides

Example 2d Ethyl4-[2-[4-[3-(methylamino)azetidine-1-carbonyl]anilino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

A solution of4-[[8-(1-ethoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino]benzoicacid (30 mg, 0.074 mmol, 1.0 equiv), tert-butylazetidine-3-ylmethylcarbamate HCl (33 mg, 0.15 mmol, 2.0 equiv), HATU(42 mg, 0.11 mmol, 1.5 equiv) and N,N-diisopropylethylamine (65 uL, 0.37mmol, 5.0 equiv) in DMF (1.0 mL) was stirred at 50° C. overnight. Thereaction mixture was concentrated under vacuum. A solution of crudeproduct in dichloromethane (1 mL) was mixed with trifluoroacetic acid(56 uL, 0.74 mmol, 10 equiv) and stirred at 50° C. overnight. Thereaction was concentrated under vacuum and the crude product waspurified by Prep-HPLC (Column, Gemini C18 100×30 mm; mobile phase,CH₃CN:NH₄OH/H₂O (10 mmol/L)=5%-85%, 10 min; flow rate, 70 mL/min;Detector, UV 254 nm) to give 5.7 mg (16%) of Ethyl4-[2-[4-[3-(methylamino)azetidine-1-carbonyl]anilino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylateas an off white solid, (Example 2-55, Table II). ¹H NMR (400 MHz,DMSO-d₆) δ 10.01 (s, 1H), 8.71 (dd, J=6.5, 1.1 Hz, 1H), 7.78-7.71 (m,2H), 7.65-7.57 (m, 2H), 7.53 (d, J=7.4 Hz, 1H), 7.32 (s, 1H), 7.06 (t,J=7.0 Hz, 1H), 4.43 (s, 1H), 4.18 (s, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.98(s, 1H), 3.65 (t, J=5.7 Hz, 2H), 3.48 (s, 1H), 3.40-3.23 (m, 1H),3.20-3.14 (m, 1H), 2.68-2.62 (m, 2H), 2.21 (s, 3H), 1.22 (t, J=7.1 Hz,3H). LCMS (method 5). Found 476.3 [M+H]⁺ Rt 3.8 min).

Example 2e4-([8-[1-(1-cyanopropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamide(Example 2-482 in Table II)

A mixture of triethylamine (49.96 mg, 0.494 mmol),N-methyl-N-(1-methylpiperidin-4-yl)-4-[[8-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]amino]benzamide(110 mg, 0.247 mmol), (2E)-but-2-enenitrile (33 mg, 0.494 mmol) inpropane-1,2,3-triol (5 mL) was heated at 80° C. for 14 h. The resultingmixture was concentrated under vacuum and the residue was purified byflash chromatography on silica gel eluting with DCM/MeOH (10/1) toafford 15.6 mg (12%) of4-([8-[1-(1-cyanopropan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amino)-N-methyl-N-(1-methylpiperidin-4-yl)benzamideas a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.94 (s, 1H), 8.68(d, J=6.0 Hz, 1H), 7.72 (d, J=8.7 Hz, 2H), 7.49 (d, J=7.2 Hz, 1H), 7.42(s, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.06-7.01 (m, 1H), 3.32-3.09 (m, 2H),2.82-2.76 (m, 1H), 2.74-2.68 (m, 9H), 2.66-2.62 (m, 2H), 2.54-2.51 (m,1H), 2.28-2.27 (m, 3H), 1.80-1.59 (m, 4H), 1.56-1.53 (m, 2H), 1.16-1.14(m, 3H). LCMS (Method 7) R_(T)=2.48 min, m/z=513.0 [M+H]⁺.

The immediately preceding Examples may be modified via conventionallyknown chemistries to provide access to other compounds that fall withinthe scope of the present invention, such as compounds of Formula 0,non-limiting examples of which are seen in Table II.

TABLE II

  Ex

  R⁸   n LCMS (ESI) m/z [M + H⁺] 2-1 

1 518 2-2  ″

1 530 2-3  ″

1 546 2-4  ″

1 528 2-5  ″

1 554 2-6  ″

1 485 2-7  ″

1 529 2-8  ″

1 536 2-9  ″

1 518 2-10  ″

1 545 2-11 

1 548 2-12 

″ 1 518 2-13 

″ 1 518 2-14 

″ 1 512 2-15 

″ 1 538 2-16 

″ 1 566 2-17 

″ 1 567 2-18 

″ 1 560 2-19 

″ 1 553 2-20 

″ 1 534 2-21 

″ 1 558 2-22 

″ 1 595 2-23 

″ 1 532 2-24 

″ 1 490 2-25 

″ 1 546 2-26 

″ 1 546 2-27 

″ 1 530 2-28 

1 568 2-29 

″ 1 596 2-30 

″ 1 558 2-31 

″ 1 516 2-32 

″ 1 571 2-33 

″ 1 558 2-34 

″ 1 596 2-35 

″ 1 554 2-36 

″ 1 556 2-37 

″ 1 570 2-38 

″ 1 568 2-39 

″ 1 584 2-40 

″ 1 568 2-41 

″ 1 564 2-42 

″ 1 564 2-43 

1 584 2-44 

1 543 2-45 

1 598 2-46 

″ 1 596 2-47 

″ 1 598 2-48 

″ 1 570 2-49 

″ 1 610 2-50 

″ 1 618 2-51 

″ 1 647 2-52 

1 485 2-53  ″

1 558 2-54  ″

1 544 2-55 

1 476 2-56 

″ 1 534 2-57 

″ 1 533 2-58 

″ 1 476 2-59 

″ 1 526 2-60 

″ 1 504 2-61 

″ 1 532 2-62 

″ 1 538 2-63 

″ 1 588 2-64 

″ 1 589 2-65 

″ 1 546 2-66 

″ 1 546 2-67 

″ 1 552 2-68 

″ 1 516 2-69 

″ 1 516 2-70 

″ 1 510 2-71 

″ 1 502 2-72 

″ 1 518 2-73 

″ 1 488 2-74 

″ 1 462 2-75 

″ 1 544 2-76 

″ 1 490 2-77 

″ 1 488 2-78 

″ 1 516 2-79 

″ 1 530 2-80 

1 542 2-81 

″ 1 568 2-82 

″ 1 598 2-83 

″ 1 612 2-84 

″ 1 556 2-85 

″ 1 542 2-86 

″ 1 570 2-87 

″ 1 568 2-88 

″ 1 598 2-89 

″ 1 614 2-90 

″ 1 662 2-91 

″ 1 647 2-92 

″ 1 647 2-93 

″ 1 610 2-94 

1 505 2-95 

1 619 2-96 

″ 1 578 2-97 

″ 1 570 2-98 

″ 1 542 2-99 

″ 1 599 2-100

″ 1 586 2-101

″ 1 584 2-102

″ 1 599 2-103

″ 1 643 2-104

″ 1 640 2-105

1 558 2-106 ″

1 503 2-107 ″

1 544 2-108 ″

1 572 2-109 ″

1 530 2-110

1 548 2-111

″ 1 518 2-112

″ 1 519 2-113

″ 1 490 2-114

″ 1 504 2-115

″ 1 518 2-116

″ 1 532 2-117

″ 1 580 2-118

″ 1 532 2-119

″ 1 526 2-120

″ 1 532 2-121

″ 1 552 2-122

″ 1 516 2-123

″ 1 532 2-124

″ 1 512 2-125

″ 1 532 2-126

″ 1 502 2-127

″ 1 518 2-128

″ 1 516 2-129

″ 1 476 2-130

″ 1 490 2-131

″ 1 544 2-132

″ 1 544 2-133

″ 1 530 2-134

″ 1 546 2-135

″ 1 530 2-136

1 582 2-137

″ 1 542 2-138

″ 1 542 2-139

″ 1 570 2-140

″ 1 644 2-141

″ 1 614 2-142

″ 1 581 2-143

″ 1 604 2-144

″ 1 586 2-145

″ 1 590 2-146

″ 1 562 2-147

″ 1 584 2-148

″ 1 564 2-149

″ 1 624 2-150

″ 1 596 2-151

″ 1 582 2-152

″ 1 578 2-153

″ 1 572 2-154

″ 1 606 2-155

″ 1 643 2-156

″ 1 604 2-157

″ 1 640 2-158

″ 1 556 2-159

″ 1 625 2-160

1 542 2-161 ″

1 570 2-162 ″

1 607 2-163 ″

1 556 2-164 ″

1 558 2-165

1 476 2-166

″ 1 552 2-167

″ 1 548 2-168

″ 1 520 2-169

″ 1 478 2-170

″ 1 526 2-171

″ 1 538 2-172

″ 1 512 2-173

″ 1 526 2-174

″ 1 526 2-175

″ 1 530 2-176

″ 1 516 2-177

″ 1 512 2-178

″ 1 512 2-179

″ 1 532 2-180

″ 1 518 2-181

″ 1 544 2-182

″ 1 544 2-183

″ 1 530 2-184

″ 1 516 2-185

″ 1 516 2-186

1 568 2-187

″ 1 582 2-188

″ 1 598 2-189

″ 1 626 2-190

″ 1 598 2-191

″ 1 596 2-192

″ 1 556 2-193

″ 1 570 2-194

″ 1 502 2-195

″ 1 542 2-196

″ 1 542 2-197

″ 1 568 2-198

″ 1 582 2-199

″ 1 564 2-200

″ 1 568 2-201

″ 1 568 2-202

″ 1 568 2-203

″ 1 622 2-204

″ 1 582 2-205

″ 1 584 2-206

″ 1 564 2-207

″ 1 528 2-208

″ 1 624 2-209

″ 1 614 2-210

″ 1 612 2-211

″ 1 584 2-212

″ 1 578 2-213

″ 1 600 2-214

″ 1 570 2-215

″ 1 618 2-216

″ 1 578 2-217

″ 1 648 2-218

″ 1 618 2-219

″ 1 578 2-220

″ 1 564 2-221

″ 1 570 2-222

1 579 2-223 ″

1 528 2-224 ″

1 504 2-225 ″

1 554 2-226

1 532 2-227

″ 1 547 2-228

″ 1 554 2-229

″ 1 526 2-230

″ 1 464 2-231

″ 1 476 2-232

″ 1 552 2-233

″ 1 490 2-234

″ 1 552 2-235

″ 1 566 2-236

″ 1 534 2-237

″ 1 526 2-238

″ 1 530 2-239

″ 1 552 2-240

″ 1 516 2-241

″ 1 588 2-242

″ 1 546 2-243

″ 1 561 2-244

″ 1 516 2-245

″ 1 512 2-246

″ 1 502 2-247

″ 1 544 2-248

″ 1 488 2-249

″ 1 518 2-250

″ 1 490 2-251

″ 1 553 2-252

″ 1 544 2-253

1 582 2-254

″ 1 598 2-255

″ 1 528 2-256

″ 1 514 2-257

″ 1 582 2-258

″ 1 582 2-259

″ 1 584 2-260

″ 1 582 2-261

″ 1 661 2-262

″ 1 655 2-263

1 542 2-264

1 557 2-265

″ 1 618 2-266

″ 1 584 2-267

″ 1 556 2-268

″ 1 600 2-269

″ 1 598 2-270

″ 1 585 2-271

″ 1 586 2-272

″ 1 590 2-273

″ 1 590 2-274

″ 1 584 2-275

″ 1 599 2-276

″ 1 599 2-277

″ 1 618 2-278

″ 1 619 2-279

″ 1 594 2-280

″ 1 604 2-281

1 542 2-282 ″

1 528 2-283 ″

1 546 2-284 ″

1 522 2-285 ″

1 581 2-286 ″

1 571 2-287 ″

1 527 2-288 ″

1 570 2-289 ″

1 516 2-290 ″

1 556 2-291

1 547 2-292

″ 1 504 2-293

″ 1 518 2-294

″ 1 518 2-295

″ 1 560 2-296

″ 1 490 2-297

″ 1 567 2-298

″ 1 573 2-299

″ 1 570 2-300

″ 1 601 2-301

″ 1 532 2-302

″ 1 544 2-303

″ 1 544 2-304

″ 1 562 2-305

″ 1 532 2-306

″ 1 530 2-307

″ 1 504 2-308

″ 1 502 2-309

″ 1 546 2-310

″ 1 516 2-311

″ 1 516 2-312

″ 1 530 2-313

1 554 2-314

″ 1 568 2-315

″ 1 582 2-316

″ 1 556 2-317

″ 1 542 2-318

″ 1 528 2-319

″ 1 542 2-320

″ 1 554 2-321

″ 1 554 2-322

″ 1 582 2-323

″ 1 540 2-324

″ 1 610 2-325

″ 1 613 2-326

″ 1 568 2-327

″ 1 627 2-328

″ 1 568 2-329

″ 1 610 2-330

″ 1 598 2-331

″ 1 586 2-332

″ 1 612 2-333

″ 1 600 2-334

″ 1 584 2-335

″ 1 556 2-336

″ 1 530 2-337

″ 1 570 2-338

″ 1 590 2-339

″ 1 612 2-340

″ 1 612 2-341

″ 1 604 2-342

″ 1 675 2-343

″ 1 564 2-344

1 488 2-345 ″

1 530 2-346 ″

1 560 2-347 ″

1 556 2-348 ″

1 556 2-349 ″

1 532 2-350 ″

1 581 2-351 ″

1 580 2-352 ″

1 530 2-353 ″

1 544 2-354

1 490 2-355

″ 1 492 2-356

″ 1 490 2-357

″ 1 490 2-358

″ 1 552 2-359

″ 1 562 2-360

″ 1 490 2-361

″ 1 512 2-362

″ 1 504 2-363

″ 1 560 2-364

″ 1 562 2-365

″ 1 546 2-366

″ 1 516 2-367

″ 1 516 2-368

″ 1 530 2-369

″ 1 558 2-370

″ 1 538 2-371

″ 1 502 2-372

″ 1 502 2-373

″ 1 530 2-374

″ 1 464 2-375

″ 1 502 2-376

″ 1 530 2-377

1 568 2-378

″ 1 582 2-379

″ 1 554 2-380

″ 1 598 2-381

″ 1 582 2-382

″ 1 596 2-383

″ 1 596 2-384

″ 1 596 2-385

″ 1 556 2-386

″ 1 554 2-387

″ 1 554 2-388

″ 1 582 2-389

″ 1 584 2-390

″ 1 640 2-391

″ 1 582 2-392

″ 1 540 2-393

″ 1 625 2-394

″ 1 619 2-395

″ 1 605 2-396

″ 1 604 2-397

″ 1 605 2-398

″ 1 582 2-399

″ 1 544 2-400

″ 1 624 2-401

″ 1 578 2-402

″ 1 564 2-403

″ 1 624 2-404

″ 1 618 2-405

″ 1 604 2-406

″ 1 606 2-407

″ 1 564 2-408

1 488 2-409 ″

1 514 2-410 ″

1 516 2-411 ″

1 532 2-412 ″

1 544 2-413 ″

1 559 2-414

1 504 2-415

″ 1 518 2-416

″ 1 518 2-417

″ 1 529 2-418

″ 1 516 2-419

″ 1 512 2-420

″ 1 504 2-421

″ 1 573 2-422

″ 1 512 2-423

″ 1 512 2-424

″ 1 552 2-425

″ 1 504 2-426

″ 1 552 2-427

″ 1 504 2-428

″ 1 518 2-429

″ 1 567 2-430

″ 1 530 2-431

″ 1 561 2-432

″ 1 530 2-433

″ 1 490 2-434

″ 1 488 2-435

″ 1 502 2-436

″ 1 530 2-437

″ 1 516 2-438

″ 1 504 2-439

″ 1 530 2-440

1 568 2-441

″ 1 516 2-442

″ 1 612 2-443

″ 1 596 2-444

″ 1 542 2-445

″ 1 542 2-446

″ 1 556 2-447

″ 1 542 2-448

″ 1 570 2-449

″ 1 540 2-450

″ 1 596 2-451

″ 1 528 2-452

″ 1 554 2-453

″ 1 584 2-454

″ 1 540 2-455

″ 1 570 2-456

″ 1 604 2-457

″ 1 613 2-458

″ 1 584 2-459

″ 1 542 2-460

″ 1 614 2-461

″ 1 624 2-462

″ 1 622 2-463

″ 1 598 2-464

″ 1 556 2-465

″ 1 572 2-466

″ 1 556 2-467

″ 1 570 2-468

″ 1 618 2-469

″ 1 568 2-470

″ 1 689 2-471

″ 1 604 2-472

″ 1 646 2-473

″ 1 632 2-474

″ 1 641 2-475

″ 1 653 2-476

″ 1 578 2-477

″ 1 632 2-478

″ 1 564 2-479

1 593 2-480

2 571 2-481

″ 0 543 2-482

1 513 2-483

1 570 2-484

″ 1 584 2-485

″ 1 584 2-486

″ 1 640

Example 3a Cyclopropanecarboxylic acid(8-Bromo-1,8a-dihydro-[1,2,4]triazolo[1,5-a]pyridine-2-yl)-amide

Cyclopropanecarboxylic acid(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide may be preparedaccording to WO 2010/010186, incorporated herein by reference, andfunctionalised using the methods described above in Examples 1 and 2.

TABLE III

LCMS (ESI) m/z Ex Q¹ Q² [M + H⁺] 3-1

391

Enzymatic Assays

JAK Enzyme Assays were Carried Out as Follows:

The activity of the isolated recombinant JAK1 and JAK2 kinase domain wasmeasured by monitoring phosphorylation of a peptide derived from JAK3(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr, fluorescently labeledon the N-terminus with 5-carboxyfluorescein) using the Caliper LabChip®technology (Caliper Life Sciences, Hopkinton, Mass.). To determineinhibition constants (K_(i)), compounds were diluted serially in DMSOand added to 50 μL kinase reactions containing purified enzyme (1.5 nMJAK1, or 0.2 nM JAK2), 100 mM HEPES buffer (pH 7.2), 0.015% Brij-35, 1.5μM peptide substrate, ATP (25 μM), 10 mM MgCl₂, 4 mM DTT at a final DMSOconcentration of 2%. Reactions were incubated at 22° C. in 384-wellpolypropylene microtiter plates for 30 minutes and then stopped byaddition of 25 μL of an EDTA containing solution (100 mM HEPES buffer(pH 7.2), 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTAconcentration of 50 mM. After termination of the kinase reaction, theproportion of phosphorylated product was determined as a fraction oftotal peptide substrate using the Caliper LabChip® 3000 according to themanufacturer's specifications. K_(i) values were then determined usingthe Morrison tight binding model (Morrison, J. F., Biochim. Biophys.Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth.Enzymol., 63:437-467 (1979)) modified for ATP-competitive inhibition[K_(i)=K_(i,app) (1+[ATP]/K_(m,app))].

JAK1 Pathway Assay in Cell Lines was Carried Out as Follows:

Inhibitor potency (EC₅₀) was determined in cell-based assays designed tomeasure JAK1 dependent STAT phosphorylation. As noted above, inhibitionof IL-4, IL-13, and IL-9 signaling by blocking the Jak/Stat signalingpathway can alleviate asthmatic symptoms in pre-clinical lunginflammation models (Mathew et al., 2001, J Exp Med 193(9): 1087-1096;Kudlacz et. al., 2008, Eur J. Pharmacol 582(1-3): 154-161).

In one assay approach, TF-1 human erythroleukemia cells obtained fromthe American Type Culture Collection (ATCC; Manassas, Va.) were used tomeasure JAK1-dependent STATE phosphorylation downstream of IL-13stimulation. Prior to use in the assays, TF-1 cells were starved ofGM-CSF overnight in OptiMEM medium (Life Technologies, Grand Island,N.Y.) supplemented with 0.5% charcoal/dextran stripped fetal bovineserum (FBS), 0.1 mM non-essential amino acids (NEAA), and 1 mM sodiumpyruvate. The assays were run in 384-well plates in serum-free OptiMEMmedium using 300,000 cells per well. In a second assay approach, BEAS-2Bhuman bronchial epithelial cells obtained from ATCC were plated at100,000 cells per well of a 96-well plate one day prior to theexperiment. The BEAS-2B assay was run in complete growth medium(bronchial epithelial basal medium plus bulletkit; Lonza; Basel,Switzerland).

Test compounds were serially diluted 1:2 in DMSO and then diluted 1:50in medium just before use. Diluted compounds were added to the cells,for a final DMSO concentration of 0.2%, and incubated for 30 min (forthe TF-1 assay) or 1 hr (for the BEAS-2B assay) at 37° C. Then, cellswere stimulated with human recombinant cytokine at their respective EC₉₀concentrations, as previously determined for each individual lot. Cellswere stimulated with IL-13 (R&D Systems, Minneapolis, Minn.) for 15 minat 37° C. The TF-1 cell reactions were stopped by the direct addition of10× lysis buffer (Cell Signaling Technologies, Danvers, Mass.), whereasthe BEAS-2B cell incubations were halted by the removal of medium andaddition of 1× lysis buffer. The resultant samples were frozen in theplates at −80° C. Compound mediated inhibition of STATE phosphorylationwas measured in the cell lysates using MesoScale Discovery (MSD)technology (Gaithersburg, Md.). EC₅₀ values were determined as theconcentration of compound required for 50% inhibition of STATphosphorylation relative to that measured for the DMSO control.

Table 4 provides JAK1 K_(i), JAK2 K_(i) and IL-13-pSTAT6 IC₅₀information for the noted Examples of the indicated Tables.

TABLE 4 IL13- IL-13- pSTAT6 JAK1 JAK2 pSTAT6 BEASB2B Table Example Ki KiIC50 IC50 number number (μM) (μM) (μM) (μM) 1 1-1  0.01672 0.00085 11-2  0.07402 0.01425 1 1-3  0.45468 0.09239 >10 1 1-4  0.08151 0.012406.5881 1 1-5  0.04475 0.00515 0.7669 1 1-6  0.26472 0.03993 3.0729 11-7  0.06210 0.00651 1 1-8  0.14044 0.02309 0.7563 1 1-9  0.488740.06321 >10 1 1-10  0.32136 0.07465 >10 1 1-11  0.02593 0.00628 0.2352 11-12  0.40601 0.07747 3.4017 1 1-13  0.05838 0.01312 0.4936 1 1-14 0.05240 0.00753 1 1-15  0.18745 0.01220 1 1-16  0.18468 0.02552 1 1-17 0.00291 0.00112 0.0339 0.1530 1 1-18  0.08788 0.01733 1 1-19  0.177750.03197 1 1-20  0.19653 0.03681 1 1-21  0.01461 0.00649 0.3330 1 1-22 0.17116 0.03212 1 1-23  0.01108 0.00250 0.0737 1 1-24  0.15679 0.01914 11-25  0.39046 0.04911 1 1-26  0.03691 0.00408 1 1-27  0.22126 0.01721 11-28  0.07039 0.00821 1 1-29  0.40172 0.04742 1 1-30  0.00170 0.000270.2523 1 1-31  0.45295 0.05243 1 1-32  0.10910 0.02875 1 1-33  0.218560.03866 1 1-34  0.01874 0.00861 0.9155 1 1-35  0.18364 0.02768 1 1-36 0.00735 0.00432 0.1422 1 1-37  0.02357 0.00670 0.0763 1 1-38  0.006860.00559 0.1517 1 1-39  0.00773 0.00352 1 1-40  0.01146 0.00458 1 1-41 0.00205 0.00020 0.0159 0.0420 1 1-42  0.91987 1.09362 1 1-43  0.031010.00784 0.9680 1 1-44  0.05244 0.00703 0.1679 1 1-45  0.19352 0.02040 11-46  0.10061 0.01013 1 1-47  0.00135 0.0103 0.0581 1 1-48  0.00230 11-49  0.00321 1 1-50  0.00311 1 1-51  0.00374 1 1-52  0.00188 0.0211 11-53  0.00103 0.0274 1 1-54  0.00115 0.1004 1 1-55  0.00319 1 1-56 0.00430 1 1-57  0.00336 1 1-58  0.00318 1 1-59  0.00127 0.0155 1 1-60 0.00106 0.0122 1 1-61  0.00253 1 1-62  0.00142 0.0228 1 1-63  0.00413 11-64  0.00227 1 1-65  0.00234 1 1-66  0.00222 1 1-67  0.00341 1 1-68 0.00216 1 1-69  0.00612 1 1-70  0.00257 1 1-71  0.00450 1 1-72  0.003531 1-73  0.01098 1 1-74  0.00134 0.0335 1 1-75  0.00248 1 1-76  0.001510.0127 1 1-77  0.00329 1 1-78  0.00326 1 1-79  0.00479 1 1-80  0.00347 11-81  0.00082 0.0109 1 1-82  0.00309 1 1-83  0.00324 1 1-84  0.00237 11-85  0.00249 1 1-86  0.00201 0.0213 1 1-87  0.00474 1 1-88  0.00270 11-89  0.00190 0.1266 1 1-90  0.00297 1 1-91  0.00255 1 1-92  0.001680.0593 1 1-93  0.00613 1 1-94  0.00258 1 1-95  0.00193 0.1148 1 1-96 0.00172 0.0646 1 1-97  0.00198 0.0250 1 1-98  0.00144 0.0119 0.0424 11-99  0.00332 1 1-100 0.00281 1 1-101 0.00194 0.0140 1 1-102 0.001730.0450 0.0547 1 1-103 0.00154 0.0238 1 1-104 0.00326 1 1-105 0.001140.0141 1 1-106 0.00227 1 1-107 0.00277 1 1-108 0.00277 1 1-109 0.00408 11-110 0.00458 1 1-111 0.00149 0.0156 1 1-112 0.01145 0.00380 1 1-1130.00164 0.0267 1 1-114 0.00186 0.0297 1 1-115 0.00302 1 1-116 0.002950.0340 1 1-117 0.00252 0.00085 0.0292 1 1-118 0.00269 0.1120 1 1-1190.00266 1 1-120 0.00510 1 1-121 0.00297 0.1311 1 1-122 0.00271 1 1-1230.00257 0.00070 0.0258 1 1-124 0.00542 1 1-125 0.00225 0.00063 0.01640.0428 1 1-126 0.00322 1 1-127 0.00199 0.0147 0.0245 1 1-128 0.00448 11-129 0.00187 0.00174 0.0377 1 1-130 0.00371 1 1-131 0.00720 1 1-1320.00279 1 1-133 0.00278 1 1-134 0.00207 1 1-135 0.00148 1 1-136 0.003421 1-137 0.00388 1 1-138 0.00153 0.00356 0.1351 1 1-139 0.00248 0.001950.0206 1 1-140 0.00488 1 1-141 0.00171 0.0579 1 1-142 0.00311 1 1-1430.00349 1 1-144 0.00424 1 1-145 0.00576 1 1-146 0.00305 1 1-147 0.002100.00141 0.0665 1 1-148 0.00565 1 1-149 0.00896 1 1-150 0.00559 1 1-1510.00280 0.1073 0.1670 1 1-152 0.00279 0.0650 1 1-153 0.00243 0.001140.0260 1 1-154 0.00198 0.00064 0.0373 1 1-155 0.00320 1 1-156 0.00651 11-157 0.00370 1 1-158 0.00401 1 1-159 0.00482 1 1-160 0.00285 1 1-1610.00199 0.0234 0.0485 1 1-162 0.00291 1 1-163 0.00257 1 1-164 0.000800.0108 1 1-165 0.00088 0.0251 1 1-166 0.00213 1 1-167 0.00179 0.002860.0121 1 1-168 0.00275 0.0226 1 1-169 0.00670 1 1-170 0.00151 0.000980.0155 1 1-171 0.01426 1 1-172 0.00303 1 1-173 0.00195 0.00245 0.0231 11-174 0.00241 0.00231 0.0311 1 1-175 0.00174 0.00092 0.1889 1 1-1760.00192 0.00207 0.2792 1 1-177 0.00208 0.00151 0.0232 1 1-178 0.001150.00107 0.0983 1 1-179 0.00169 0.0843 1 1-180 0.00164 0.3219 1 1-1810.00140 0.1812 1 1-182 0.00259 1 1-183 0.00177 0.5361 1 1-184 0.001150.1273 1 1-185 0.00218 1 1-186 0.00203 1.0299 1 1-187 0.00147 0.4620 11-188 0.00135 0.0347 1 1-189 1 1-190 1 1-191 1 1-192 1 1-193 0.001950.2487 1 1-194 0.00352 1 1-195 0.00374 1 1-196 0.00164 0.0531 1 1-1970.00163 0.1575 1 1-198 0.00157 0.0685 1 1-199 0.00066 0.1061 1 1-2000.00360 1 1-201 0.00254 1 1-202 0.00335 1 1-203 0.00148 0.3424 1 1-2040.00408 1 1-205 0.00189 0.5215 1 1-206 0.00234 1 1-207 0.00197 0.1915 11-208 0.00231 1 1-209 0.00563 1 1-210 0.00091 0.0435 1 1-211 0.00219 11-212 0.00188 0.1962 1 1-213 0.00280 1 1-214 0.00253 1 1-215 0.00228 11-216 0.00234 1 1-217 0.00230 1 1-218 0.00192 0.1647 1 1-219 0.00260 11-220 0.00131 0.6369 1 1-221 0.00117 0.8665 1 1-222 0.00212 1 1-2230.00354 1 1-224 0.00095 0.1109 1 1-225 0.00179 0.0308 1 1-226 0.001810.0794 1 1-227 0.00285 1 1-228 0.00216 1 1-229 0.00294 1 1-230 0.002630.0581 1 1-231 0.00178 0.9157 1 1-232 0.00283 1 1-233 0.00258 0.1645 11-234 0.00193 0.0361 1 1-235 0.00186 0.3105 1 1-236 0.00256 1 1-2370.00147 0.0107 1 1-238 0.00173 0.1805 1 1-239 0.00355 1 1-240 0.00372 11-241 0.00163 0.1154 1 1-242 0.00251 1 1-243 0.00252 1 1-244 0.00270 11-245 0.00261 1 1-246 0.00036 0.00033 0.0054 0.0892 1 1-247 0.000500.00033 0.0184 0.1150 1 1-248 0.10335 0.02210 1 1-249 0.37191 0.05267 11-250 0.00393 0.00129 0.732 1 1-251 0.00061 0.00041 0.0566 1 1-2520.00048 0.00050 0.0902 1 1-253 0.00116 0.00092 0.4177 1 1-254 0.000640.00039 0.0899 0.661 1 1-255 0.00085 0.00035 0.0271 0.159 1 1-2560.00117 0.00069 0.0563 0.426 1 1-257 0.02663 0.00234 1 1-258 0.001810.00052 0.0934 1.44 1 1-259 0.02629 0.01070 1 1-260 0.10551 0.01633 11-261 0.04149 0.00356 1 1-262 0.00222 0.00064 0.1201 1 1-263 0.000820.00096 0.0182 1 1-264 0.13357 0.12124 1 1-265 0.00084 0.00057 0.0948 11-266 0.00880 0.00254 1 1-267 0.00042 0.00025 0.0324 1 1-268 0.000710.00038 0.0562 1 1-269 0.02853 0.01321 1 1-270 0.00064 0.00045 0.114 11-271 0.00088 0.00094 0.1125 0.533 1 1-272 0.00048 0.00039 0.0487 0.1721 1-273 0.00059 0.00044 0.1525 0.259 1 1-274 0.00020 0.00017 0.00790.0289 1 1-275 0.00021 0.00014 0.003 0.0555 1 1-276 0.00085 0.000480.0957 0.082 1 1-277 0.00039 0.00024 0.0231 0.0733 1 1-278 0.000330.00023 0.0163 0.0376 1 1-279 0.00041 0.00025 0.0281 0.0346 1 1-2800.00030 0.00023 0.1245 0.0528 1 1-281 0.00063 0.00039 0.0702 0.134 11-282 0.00037 0.00021 0.0426 0.0556 1 1-283 0.00018 0.00015 0.01550.0313 1 1-284 0.00057 0.00049 0.0177 0.031 1 1-285 0.00056 0.000550.0221 0.0576 1 1-286 0.00027 0.00026 0.0067 0.0762 1 1-287 0.000540.00039 0.0225 0.0364 1 1-288 0.00051 0.00040 0.028 0.0677 1 1-2890.00026 0.00042 0.0081 1 1-290 0.00018 0.00030 0.0059 1 1-291 0.000180.00036 0.525 1 1-292 0.14231 0.01850 1 1-293 0.17252 0.11010 1 1-2940.00068 0.00040 0.0627 1 1-295 0.00738 0.01611 0.729 1 1-296 0.000130.00020 0.0126 1 1-297 0.00170 0.00944 0.0367 1 1-298 0.00063 0.000450.1252 1 1-299 0.00103 0.00057 0.0557 1 1-300 0.00123 0.00055 0.0263 11-301 0.00123 0.00032 0.1792 1 1-302 0.0222 0.00637 1 1-303 0.0460.00498 2 2-1  0.00525 0.00107 0.0237 2 2-2  0.00499 0.00081 0.0340 22-3  0.00226 0.00074 0.1630 2 2-4  0.00327 0.00062 0.0466 2 2-5  0.002230.00044 1.0911 2 2-6  0.00223 0.00038 0.5846 2 2-7  0.00114 0.000250.0429 2 2-8  0.04210 0.01367 0.8488 2 2-9  0.00876 0.00148 0.6195 22-10  0.05312 0.01562 2 2-11  0.00194 0.0067 2 2-12  0.00271 2 2-13 0.00154 0.00244 0.3382 2 2-14  0.00251 2 2-15  0.00128 0.00066 0.0171 22-16  0.00267 2 2-17  0.00267 2 2-18  0.00219 0.1340 2 2-19  0.001900.00033 0.0557 2 2-20  0.00162 0.00145 0.2562 2 2-21  0.00285 2 2-22 0.00760 2 2-23  0.00379 2 2-24  0.00156 0.00098 0.0216 2 2-25  0.00285 22-26  0.00305 2 2-27  0.00163 0.00116 0.2568 2 2-28  0.00142 0.2074 22-29  0.00149 0.0803 2 2-30  0.00143 0.0403 2 2-31  0.00151 0.1811 22-32  0.00138 0.5361 2 2-33  0.00063 0.0233 2 2-34  0.00193 0.3523 22-35  0.00082 0.0950 2 2-36  0.00229 2 2-37  0.00116 0.0854 2 2-38 0.00121 0.00056 0.0029 0.0286 2 2-39  0.00179 0.0347 2 2-40  0.000510.00046 0.0035 0.0187 2 2-41  0.00058 0.0052 2 2-42  0.00056 0.000400.0047 2 2-43  0.00258 0.00136 0.0278 2 2-44  0.00070 0.00050 0.0482 22-45  0.00113 0.00038 0.0090 2 2-46  0.00140 0.00043 0.0205 2 2-47 0.00073 0.00060 0.0157 2 2-48  0.00071 0.00067 0.0335 2 2-49  0.000610.00058 0.0038 0.0102 2 2-50  0.00121 0.00058 0.0651 2 2-51  0.001400.00060 0.0702 2 2-52  0.00619 0.00183 0.0600 2 2-53  0.01531 0.00271 22-54  0.00329 0.00076 0.0163 2 2-55  0.00175 0.00117 0.0100 2 2-56 0.00142 0.00086 0.0067 0.0594 2 2-57  0.00275 2 2-58  0.00269 2 2-59 0.00239 2 2-60  0.00129 0.00096 0.0204 2 2-61  0.00364 2 2-62  0.001090.00041 0.0300 2 2-63  0.00284 0.1510 2 2-64  0.00277 2 2-65  0.00257 22-66  0.00241 0.2240 2 2-67  0.00294 0.0409 2 2-68  0.00112 0.000920.0119 2 2-69  0.00410 2 2-70  0.00194 0.00080 0.0298 2 2-71  0.00604 22-72  0.00501 2 2-73  0.00258 2 2-74  0.00082 0.00101 0.0189 2 2-75 0.00893 2 2-76  0.00508 2 2-77  0.00072 0.00109 0.1340 2 2-78  0.001360.00099 0.3603 2 2-79  0.00280 2 2-80  0.00067 0.0794 2 2-81  0.001570.0600 2 2-82  0.00141 0.2235 2 2-83  0.00126 0.1971 2 2-84  0.000930.0714 2 2-85  0.00051 0.0626 2 2-86  0.00159 0.2155 2 2-87  0.001490.0086 2 2-88  0.00225 2 2-89  0.00218 2 2-90  0.00299 2 2-91  0.00367 22-92  0.00044 0.0209 2 2-93  0.00127 0.00093 0.0047 2 2-94  0.001680.00105 0.0236 2 2-95  0.00075 0.00034 0.0043 2 2-96  0.00068 0.000340.0052 2 2-97  0.00107 0.00021 0.0137 2 2-98  0.00111 0.00034 0.0115 22-99  0.00058 0.00050 0.0294 2 2-100 0.00065 0.00064 0.0847 2 2-1010.00081 0.00074 0.0035 0.0318 2 2-102 0.00084 0.00035 0.0337 2 2-1030.00269 0.00132 0.1453 2 2-104 0.00194 0.00044 0.0597 2 2-105 0.007570.00144 0.3728 2 2-106 0.03856 0.00729 8.5694 2 2-107 0.00550 0.001040.4219 2 2-108 0.00137 0.00050 0.0098 2 2-109 0.00502 0.00098 0.0343 22-110 0.00327 2 2-111 0.00159 0.00106 0.0226 2 2-112 0.00170 0.001470.2326 2 2-113 0.00142 0.00109 0.0968 2 2-114 0.00173 0.00140 0.0692 22-115 0.00129 0.00092 0.0190 2 2-116 0.00214 2 2-117 0.00457 2 2-1180.00348 2 2-119 0.00168 0.00067 0.0239 2 2-120 0.00878 2 2-121 0.00223 22-122 0.00474 2 2-123 0.00194 0.00067 0.0488 2 2-124 0.00134 0.000850.0385 2 2-125 0.00382 2 2-126 0.00233 2 2-127 0.00313 2 2-128 0.00273 22-129 0.00402 2 2-130 0.00128 0.00109 0.2256 2 2-131 0.00287 2 2-1320.00239 2 2-133 0.00265 2 2-134 0.00235 2 2-135 0.00299 2 2-136 0.001700.1631 2 2-137 0.00083 0.00079 0.0788 2 2-138 0.00047 0.0619 2 2-1390.00118 0.3584 2 2-140 0.00429 2 2-141 0.00299 2 2-142 0.00118 0.0066 22-143 0.00091 0.0079 2 2-144 0.00098 0.1870 2 2-145 0.00066 0.0064 22-146 0.00163 0.0065 2 2-147 0.00681 0.0066 2 2-148 0.00044 0.000510.0032 0.0150 2 2-149 0.00087 0.00040 0.0107 2 2-150 0.00125 0.000870.0083 2 2-151 0.00149 0.00036 0.0057 2 2-152 0.00167 0.00049 0.0093 22-153 0.00103 0.00030 0.0286 2 2-154 0.00091 0.00055 0.0045 0.0806 22-155 0.00151 0.00060 0.1317 2 2-156 0.00056 0.00020 0.0083 2 2-1570.00071 0.00027 0.0047 2 2-158 0.00105 0.0073 2 2-159 0.00041 0.000440.0351 2 2-160 0.01113 0.00151 0.0470 2 2-161 0.00838 0.00172 0.0442 22-162 0.03732 0.00652 2 2-163 0.00135 0.00029 0.0284 2 2-164 0.015020.00217 2 2-165 0.00161 0.00121 0.1874 2 2-166 0.00357 2 2-167 0.001980.0158 2 2-168 0.00253 2 2-169 0.00274 2 2-170 0.00139 0.00086 0.0148 22-171 0.00351 2 2-172 0.00153 0.00082 0.0120 2 2-173 0.00496 2 2-1740.00251 2 2-175 0.00119 0.00077 0.0122 2 2-176 0.00141 0.00078 0.0081 22-177 0.00087 0.00054 0.0154 2 2-178 0.00097 0.00057 0.0326 2 2-1790.00234 2 2-180 0.00556 2 2-181 0.00274 2 2-182 0.00320 2 2-183 0.003352 2-184 0.00351 2 2-185 0.00093 0.00095 0.0299 2 2-186 0.00135 0.0233 22-187 0.00160 0.6517 2 2-188 0.00068 0.2390 2 2-189 0.00088 0.1096 22-190 0.00176 0.0409 2 2-191 0.00133 0.0637 2 2-192 0.00058 0.2133 22-193 0.00150 0.2781 2 2-194 0.00154 0.0942 2 2-195 0.00066 0.1629 22-196 0.00111 0.0299 2 2-197 0.00171 0.2953 2 2-198 0.00145 0.0539 22-199 0.00104 0.00050 0.0042 2 2-200 0.00185 0.00058 0.0041 2 2-2010.00186 0.0060 2 2-202 0.00104 0.0115 2 2-203 0.00152 0.0301 2 2-2040.00056 0.0897 2 2-205 0.00122 0.0100 2 2-206 0.00458 0.00734 0.0034 22-207 0.00223 0.1412 2 2-208 0.00095 0.00036 0.0044 2 2-209 0.001990.00095 0.0299 2 2-210 0.00081 0.00029 0.0069 0.0456 2 2-211 0.001320.00056 0.0071 2 2-212 0.00091 0.00023 0.0080 2 2-213 0.00075 0.000580.0056 0.0206 2 2-214 0.00061 0.00070 0.0055 2 2-215 0.00055 0.000210.0135 2 2-216 0.00078 0.00043 0.0074 2 2-217 0.00076 0.00033 0.0095 22-218 0.00099 0.00044 0.0154 2 2-219 0.00066 0.00028 0.0033 0.0372 22-220 0.00057 0.00039 0.0058 2 2-221 2 2-222 0.00413 0.00156 0.4679 22-223 0.00136 0.00035 0.0173 2 2-224 0.01502 0.00279 0.2044 2 2-2250.00129 0.00035 0.0113 2 2-226 0.00337 2 2-227 0.00371 2 2-228 0.00320 22-229 0.00339 2 2-230 0.00240 0.00096 0.1574 2 2-231 0.00139 0.001140.2677 2 2-232 0.00210 0.00115 0.2879 2 2-233 0.00280 2 2-234 0.00372 22-235 0.00168 0.00047 0.0231 2 2-236 0.00294 2 2-237 0.00237 2 2-2380.00288 2 2-239 0.00321 2 2-240 2 2-241 0.00108 0.00061 0.0637 2 2-2420.00640 2 2-243 0.00547 2 2-244 0.00328 2 2-245 0.00304 0.00074 0.0122 22-246 0.00209 0.00074 2 2-247 0.00437 2 2-248 0.00413 2 2-249 0.01960 22-250 0.00134 0.00103 0.0767 2 2-251 0.00369 2 2-252 0.00234 2 2-2530.00143 0.1513 2 2-254 0.00137 0.5875 2 2-255 0.00286 0.2970 2 2-2560.00067 0.0684 2 2-257 0.00187 0.0605 2 2-258 0.00194 0.2379 2 2-2590.00097 0.0058 2 2-260 0.00183 0.0053 2 2-261 0.00167 0.0465 2 2-2620.00091 0.0971 2 2-263 0.00143 0.00065 0.0296 2 2-264 0.00081 0.000710.0117 2 2-265 0.00056 0.00026 0.0042 2 2-266 0.00134 0.00039 0.0097 22-267 0.00161 0.00075 0.0087 2 2-268 0.00060 0.00048 0.0030 0.0266 22-269 0.00088 0.00071 0.0051 2 2-270 0.00062 0.00079 0.0164 2 2-2710.00048 0.00045 0.0053 0.0159 2 2-272 0.00076 0.00046 0.0039 0.1065 22-273 0.00049 0.00035 0.0055 2 2-274 0.00062 0.00076 0.0450 2 2-2750.00115 0.00053 0.0372 2 2-276 0.00129 0.00066 0.1290 2 2-277 0.000680.00023 0.0198 2 2-278 0.00121 0.00008 0.0393 2 2-279 0.00076 0.000390.0388 2 2-280 0.00067 0.00026 0.0095 2 2-281 0.00253 0.00066 0.0394 22-282 0.00261 0.00045 0.0464 2 2-283 0.00465 0.00085 0.0540 2 2-2840.01229 0.00135 0.1629 2 2-285 0.00643 0.00187 0.7389 2 2-286 0.008990.00172 1.7549 2 2-287 0.00110 0.00022 0.2475 2 2-288 0.00132 0.000440.0127 0.0777 2 2-289 0.00578 0.00101 0.0429 2 2-290 0.00164 0.000440.0377 2 2-291 0.00190 0.00135 0.0223 2 2-292 0.00527 2 2-293 0.001260.00121 0.0295 2 2-294 0.00315 2 2-295 0.00327 2 2-296 0.00173 0.001280.3831 2 2-297 0.00205 0.00033 2 2-298 0.00308 2 2-299 0.00305 2 2-300 22-301 0.00371 2 2-302 0.00348 2 2-303 0.00361 2 2-304 0.00624 2 2-3050.00384 2 2-306 0.00144 0.00116 0.4378 2 2-307 0.00265 2 2-308 0.001980.00089 0.0761 2 2-309 0.00209 2 2-310 0.00387 2 2-311 0.00686 0.00093 22-312 0.00206 0.00087 2 2-313 0.00157 0.1836 2 2-314 0.00063 0.1939 22-315 0.00173 0.1089 2 2-316 0.00069 0.1448 2 2-317 0.00303 0.003990.2284 2 2-318 0.00065 0.0377 2 2-319 0.00057 0.0243 2 2-320 0.000760.1199 2 2-321 0.00078 0.2500 2 2-322 0.00086 0.1040 2 2-323 0.001440.0175 2 2-324 0.00105 0.0082 2 2-325 0.00159 0.1910 2 2-326 0.000980.00066 0.0042 2 2-327 0.00180 0.0199 2 2-328 0.00050 0.0123 2 2-3290.00091 0.00042 0.0083 2 2-330 0.00162 0.00073 0.0134 2 2-331 0.001180.00032 0.0089 2 2-332 0.00051 0.00062 0.0092 2 2-333 0.00101 0.000390.0055 2 2-334 0.00105 0.00062 0.0043 0.0307 2 2-335 0.00061 0.000640.0143 2 2-336 0.00085 0.00085 0.0086 2 2-337 0.00057 0.00061 0.0289 22-338 0.00040 0.00022 0.0033 0.0234 2 2-339 0.00116 0.00037 0.0098 22-340 0.00095 0.00031 0.0039 2 2-341 0.00084 0.00038 0.0114 2 2-3420.00074 0.00032 0.0162 2 2-343 0.00061 0.00037 0.0046 0.0383 2 2-3440.01982 0.00369 1.7992 2 2-345 0.00531 0.00153 0.0237 2 2-346 0.004520.00099 0.0891 2 2-347 0.00110 0.00033 0.0175 0.0411 2 2-348 0.004930.00154 0.0347 2 2-349 0.00346 0.00087 0.0216 2 2-350 0.01759 0.004810.7190 2 2-351 0.00195 0.00077 0.0526 2 2-352 0.00557 0.00077 0.0342 22-353 0.00262 0.00079 0.0327 2 2-354 0.00385 2 2-355 0.00302 2 2-3560.00613 2 2-357 0.00393 2 2-358 0.00199 0.0413 2 2-359 0.00611 2 2-3600.00132 0.00108 0.4112 2 2-361 0.00170 0.00061 0.0089 2 2-362 0.001750.00133 0.2286 2 2-363 0.00267 2 2-364 0.00569 2 2-365 0.00434 2 2-3660.00366 2 2-367 0.00462 2 2-368 0.00357 2 2-369 0.00262 2 2-370 2 2-3710.00268 2 2-372 0.00137 0.00100 0.2962 2 2-373 0.00276 2 2-374 0.002520.00158 0.0625 2 2-375 0.00318 2 2-376 0.00254 2 2-377 0.00110 0.0555 22-378 0.00153 0.2376 2 2-379 0.00146 0.2821 2 2-380 0.00141 0.0384 22-381 2 2-382 0.00115 0.3755 2 2-383 0.00155 0.0090 2 2-384 0.001730.0930 2 2-385 0.00106 0.1738 2 2-386 0.00121 0.1548 2 2-387 0.000880.1472 2 2-388 0.00114 0.1413 2 2-389 0.00134 0.0126 2 2-390 0.002020.1779 2 2-391 0.00071 0.0057 2 2-392 0.00118 0.2170 2 2-393 0.000960.00039 0.0234 2 2-394 0.00063 0.00024 0.0040 2 2-395 0.00065 0.000180.0046 2 2-396 0.00097 0.00044 0.0054 2 2-397 0.00118 0.00034 0.0202 22-398 0.00239 0.00068 0.0086 2 2-399 0.00128 0.00079 0.0121 2 2-4000.00135 0.00095 0.0068 2 2-401 0.00058 0.00034 0.0060 2 2-402 0.000600.00029 0.0056 2 2-403 0.00085 0.00037 0.0074 2 2-404 0.00060 0.000240.0132 2 2-405 0.00060 0.00027 0.0075 2 2-406 0.00112 0.00062 0.0404 22-407 0.00063 0.00028 0.0047 2 2-408 0.02337 0.00422 0.1878 2 2-4090.00400 0.00112 0.1243 2 2-410 0.00912 0.00155 0.1299 2 2-411 0.006670.00197 0.3481 2 2-412 0.00435 0.00070 0.0265 2 2-413 0.01955 0.003591.2609 2 2-414 0.00320 2 2-415 0.00171 0.00132 0.0130 2 2-416 0.001640.00125 0.5977 2 2-417 0.00123 0.00045 0.0143 2 2-418 0.00329 2 2-4190.00510 2 2-420 0.00289 2 2-421 0.00131 0.00082 0.0241 2 2-422 0.001800.0140 2 2-423 0.00190 0.00088 0.0173 2 2-424 0.00225 2 2-425 0.000850.00100 0.2262 2 2-426 0.00189 0.00055 0.0510 2 2-427 0.00101 0.000980.2152 2 2-428 0.00168 0.00115 0.4627 2 2-429 0.00126 0.00068 0.0274 22-430 0.00479 2 2-431 0.00679 2 2-432 0.00164 0.00062 0.0430 2 2-4330.00121 0.00112 0.0132 2 2-434 0.00155 0.00114 0.2315 2 2-435 0.00233 22-436 0.00299 2 2-437 0.00179 0.00114 0.0337 2 2-438 0.00403 2 2-4390.00289 2 2-440 0.00047 0.1555 2 2-441 0.00053 0.0824 2 2-442 0.000880.3050 2 2-443 0.00120 0.0723 2 2-444 0.00092 0.00090 0.1538 2 2-4450.00127 0.06143 0.4557 2 2-446 0.00040 0.2085 2 2-447 0.00090 0.2752 22-448 0.00103 0.1198 2 2-449 0.00117 0.3546 2 2-450 0.00177 0.1152 22-451 0.00146 0.2871 2 2-452 0.00097 0.1343 2 2-453 0.00123 0.1713 22-454 0.00057 0.0879 2 2-455 0.00123 0.0055 2 2-456 0.00092 0.0075 22-457 0.00259 2 2-458 0.00115 0.0459 2 2-459 0.00061 0.0205 2 2-4600.00093 0.0276 2 2-461 0.00084 0.00030 0.0061 2 2-462 0.00087 0.000290.0444 2 2-463 0.00116 0.00065 0.0260 2 2-464 0.00108 0.00044 0.0091 22-465 0.00052 0.00073 0.0094 2 2-466 0.00097 0.00079 0.0179 2 2-4670.00164 0.00068 0.0209 2 2-468 0.00069 0.00026 0.0128 2 2-469 0.000680.00076 0.0838 2 2-470 0.00075 0.00033 0.0130 2 2-471 0.00083 0.000400.0064 2 2-472 0.00182 0.00062 0.0679 2 2-473 0.00261 0.00139 0.0481 22-474 0.00100 0.00029 0.0141 2 2-475 0.00075 0.00038 0.0429 2 2-4760.00092 0.00042 0.0105 2 2-477 0.00157 0.00080 0.1128 2 2-478 0.000760.00043 0.0048 2 2-479 0.01796 0.00310 0.2390 2 2-480 0.00446 0.000850.1779 2 2-481 0.26562 0.05267 3 3-1  0.10799 0.14510 Blank: notdetermined

What is claimed is:
 1. A compound of Formula 0:

and stereoisomers and salts thereof, wherein: Ar¹ is phenylene or 3-11membered heteroarylene, wherein Ar¹ is optionally substituted; X is —O—or —N(R^(1b))—(CR^(x1)R^(y1))_(p)—, wherein R^(x1) and R^(y1) are eachindependently hydrogen or C₁-C₆ alkyl and p is 0 to 6, and wherein the—N(R^(1b))— portion of —N(R^(1b))—(CR^(x1)R^(y1))_(p)— is bound to thecarbonyl carbon of Formula 0; R^(1a) is hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, phenyl, or 3-11 membered heterocyclyl and R^(1a) isoptionally substituted by R⁹; R^(1b) is hydrogen, C₁-C₆ alkyl, or C₃-C₈cycloalkyl, and wherein one or more alkylene units of said alkyl groupis optionally substituted by —O— and wherein any alkyl or cycloalkylgroup is optionally substituted by OH, or when p is 0 and X is—N(R^(1b))—, R^(1a) and R^(1b) may be joined together with the nitrogenatom to which R^(1a) and R^(1b) is attached to form a 3-11 memberedheterocyclyl optionally substituted by R⁹; R² is a 3-11 memberedheterocyclyl containing at least 1 nitrogen, selected from groups(a)-(e) and (h)-(j), or a C₅-C₈ cycloalkenyl ring (f), or a—O—(CR^(x)R^(y))_(q)—Ar² group (g) where R^(x) and R^(y) areindependently hydrogen or C₁-C₆ alkyl, q is 0 to 3 and Ar² is optionallysubstituted C₆-C₁₀ aryl or optionally substituted 5-11 memberedheteroaryl:

R³, R⁴ and R⁵ are each independently selected from the group consistingof hydrogen, CH₃, CH₂CH₃, OCH₃, CF₃, F and Cl; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen, halogen,OH, CN, phenyl, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, (C₀-C₆alkylene)3-11 membered heterocyclyl, (C₀-C₆ alkylene)C(O)NR^(a)R^(b),(C₀-C₆ alkylene)NR^(a)C(O)(C₁-C₆ alkyl), (C₀-C₆alkylene)NR^(a)C(O)(phenyl), (C₀-C₆ alkylene)C(O)R^(8a), (C₀-C₆alkylene)C(O)OR^(8a), C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆alkylene)C(O)NR^(a)R^(b), —C═N—O—(C₁-C₆ alkyl), —O—(C₁-C₆ alkyl)3-11membered heterocyclyl, (C₀-C₆ alkylene)NR^(a)SO₂(C₁-C₆ alkyl), (C₀-C₆alkylene)NR^(a)SO₂(phenyl), and —O-(3-11 membered heterocyclyl); whereinsaid alkyl, alkylene, alkoxy, cycloalkyl, phenyl and heterocyclyl areeach independently optionally substituted, or R₆ and R₇ together form anoptionally substituted phenyl or optionally substituted 3-11 memberedheterocyclyl; R⁸ is H, C₁-C₆ alkyl, (C₀-C₆ alkylene)phenyl, (C₀-C₆alkylene)C₃-C₈ cycloalkyl, (C₀-C₆ alkylene)3-11 membered heterocyclyl,C(O)NR^(a)R^(b), SO₂NR^(a)R^(b), (C₁-C₆ alkylene)C(O)OR^(8a) orC(O)R^(8a), wherein said alkyl, alkylene, heterocyclyl and phenyl areeach independently optionally substituted; R^(8a) is H, NR^(a)R^(b),C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, (C₀-C₆ alkylene)phenyl,or (C₀-C₆ alkylene)3-11 membered heterocyclyl, wherein said alkyl,alkylene, cycloalkyl, phenyl and heterocyclyl are each independentlyoptionally substituted; R^(8aa) is H, C₁-C₆ alkyl optionally substitutedby OH, or C(O)NR^(a)R^(b); or or R⁸ and R^(8aa) together form anoptionally substituted 3-11 membered heterocyclyl; R⁹, independently ateach occurrence, is OH, halogen, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, (C₀-C₆ alkylene)phenyl, (C₀-C₆ alkylene)3-11 memberedheterocyclyl, (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆alkylene)NR^(a)R^(b), or C(O)(C₁-C₆ alkyl), wherein said alkyl,alkylene, cycloalkyl, phenyl and heterocyclyl are each independentlyoptionally substituted; R^(a) and R^(b), independently at eachoccurrence, are selected from the group consisting of hydrogen, C₁-C₆alkyl optionally substituted by halogen or CN, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, or (C₀-C₆ alkylene)phenyl, and wherein one or more alkyleneunits of any alkyl group is independently optionally substituted by —O—,or alternatively R^(a) and R^(b) may be joined together with thenitrogen atom to which they are attached to form an optionallysubstituted 3-11 membered heterocyclyl; m¹, m², m³ and m⁴ are eachindependently 0, 1 or 2; and n is 0 or
 1. 2. The compound of claim 1,further defined as a compound of Formula Ia:

wherein Ar¹, X, R^(1a), R³-R⁷, m¹, m² and n are as defined in claim 1.3. The compound of claim 1, wherein

is selected from

wherein R^(7a) is selected from hydrogen, halogen, OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl and —CN.
 4. The compound of claim 1,further defined as a compound of Formula Ib:

wherein Ar¹, X, R^(1a), R³-R⁷, m¹, m² and n are as defined in claim 1.5. The compound of claim 4, wherein

is selected from

wherein R^(7a) is selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl and CN.
 6. The compound of claim 1, further defined as acompound of Formula Ic:

wherein Ar¹, X, R^(1a), R³-R⁵, R⁸, m³, m⁴ and n are as defined inclaim
 1. 7. The compound of claim 6, wherein

is selected from


8. The compound of claim 1, further defined as a compound of Formula Id:

wherein Ar¹, R^(1a), R^(1b), R³-R⁵, R⁸, m³, m⁴ and n are as defined inclaim
 1. 9. The compound of claim 1, further defined as a compound ofFormula Ie:

wherein Ar¹, R^(1a), R^(1b), R³-R⁶, R⁸, m³, m⁴ and n are as defined inclaim
 1. 10. The compound of claim 1, further defined as a compoundFormula If:

wherein Ar¹, R^(1a), R^(1b), R³-R⁷, m³, m⁴ and n are as defined inclaim
 1. 11. The compound of claim 1, further defined as a compound ofFormula Ig:

wherein Ar¹, R^(1a), R^(1b), R³-R⁵, R^(7a) and n are as defined in claim1, lea is selected from hydrogen, OH, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, (C₁-C₆ alkyl)phenyl, C₁-C₆ haloalkyl, oxo and CN, and q iseither 0 or 1, and when q is 1, then Rx and Ry are hydrogen.
 12. Acompound of claim 1, wherein R³, R⁴ and R⁵ are each hydrogen.
 13. Thecompound of claim 1, wherein Ar¹ is phenylene or pyrazolylene.
 14. Thecompound of claim 1, wherein the moiety

is further defined as


15. The compound of claim 1, wherein —X—R^(1a) is—N(R^(1b))—(CR^(x1)R^(y1))_(p)—R^(1a).
 16. The compound of claim 15,wherein: (1) R^(1b) is C₁-C₆ alkyl optionally substituted by C₁-C₆alkoxy, p is 0-3, R^(x1) and R^(y1) are each independently hydrogen orC₁-C₆ alkyl, R^(1a) is C₁-C₆ alkyl and R⁹ is NR^(a)R^(b); or (2) R^(1b)is C₁-C₆ alkyl optionally substituted by C₁-C₆ alkoxy, p is 0-3, R^(x1)and R^(y1) are each independently hydrogen or C₁-C₆ alkyl, and R^(1a) is3-11 membered heterocyclyl optionally substituted by R⁹; or (3) p is 0and R^(1a) and R^(1b) are joined to form a 3-11 membered heterocyclyloptionally substituted by R⁹.
 17. The compound of claim 1, wherein theoptional substituents of said optionally substituted C₁-C₆ alkyl of R⁹or optionally substituted 3-11 membered heterocyclyl of R⁹ are selectedfrom OH; halogen; CN; NR^(a)R^(b); C₁-C₆ alkyl optionally substituted byhalogen; C₃-C₈ cycloalkyl; C₁-C₆ alkoxy; phenyl; 3-11 memberedheterocyclyl optionally substituted by C₁-C₆ alkyl or NR^(a)R^(b);C(O)C₁-C₆ alkyl; and C(O)-3-11 membered heterocyclyl optionallysubstituted by C₁-C₆ alkyl.
 18. The compound of claim 15, wherein—N(R^(1b))—(CR^(x1)R^(y1))_(p)—R^(1a) is selected from


19. The compound of claim 15, wherein R^(1b) is hydrogen or CH₃.
 20. Acompound of Formula II:

and stereoisomers and salts thereof, wherein: Q¹ is a 3-11 memberedheterocyclyl containing at least 1 nitrogen, selected from groups(a)-(e) and (h)-(j), or a C₅-C₈ cycloalkenyl ring (f), or a—O—(CR^(x)R^(y))_(q)—Ar² group (g) where R^(x) and R^(y) areindependently hydrogen or C₁-C₆ alkyl, q is 0 to 3 and Ar² is optionallysubstituted C₆-C₁₀ aryl or optionally substituted 3-11 memberedheteroaryl:

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen, halogen, OH, CN, phenyl, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, (C₀-C₆ alkylene)3-11 membered heterocyclyl, (C₀-C₆alkylene)C(O)NR^(a)R^(b), (C₀-C₆ alkylene)NR^(a)C(O)(C₁-C₆ alkyl),(C₀-C₆ alkylene)C(O)R^(8a), (C₀-C₆ alkylene)C(O)OR^(8a), C₁-C₆ alkoxy,—O—(C₃-C₆ cycloalkyl), —O—(C₀-C₆ alkylene)C(O)NR^(a)R^(b), and —O-(3-11membered heterocyclyl); wherein said alkyl, alkylene, alkoxy,cycloalkyl, phenyl and heterocyclyl are each independently optionallysubstituted, or R₆ and R₇ together form an optionally substituted phenylor optionally substituted 3-11 membered heterocyclyl; R⁸ is C₁-C₆ alkyl,(C₀-C₆ alkylene)phenyl, C(O)NR^(a)R^(b), SO₂NR^(a)R^(b), C(O)OR^(8a) orC(O)R^(8a), wherein said alkyl, alkylene and phenyl are eachindependently optionally substituted; R^(8a) is C₁-C₆ alkyl, (C₀-C₆alkylene)C₃-C₈ cycloalkyl, (C₀-C₆ alkylene)phenyl, or (C₀-C₆alkylene)3-11 membered heterocyclyl, wherein said alkyl, alkylene,cycloalkyl, phenyl and heterocyclyl are each independently optionallysubstituted; R^(8aa) is H; or or R⁸ and R^(8aa) together form anoptionally substituted 3-11 membered heterocyclyl; R⁹, independently ateach occurrence, is OH, halogen, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈cycloalkyl, (C₀-C₆ alkylene)phenyl, (C₀-C₆ alkylene)3-11 memberedheterocyclyl, (C₀-C₆ alkylene)C(O)NR^(a)R^(b), (C₀-C₆alkylene)NR^(a)R^(b), or C(O)(C₁-C₆ alkyl), wherein said alkyl,cycloalkyl, phenyl and heterocyclyl are each independently optionallysubstituted; R^(a) and R^(b) are independently at each occurrencehydrogen, C₁-C₆ alkyl, (C₀-C₆ alkylene)C₃-C₈ cycloalkyl, or (C₀-C₆alkylene)phenyl, and wherein one or more alkylene units of any alkylgroup is independently optionally substituted by —O—, or alternativelyR^(a) and R^(b) may be joined together with the nitrogen atom to whichthey are attached to form an optionally substituted 3-11 memberedheterocyclyl; m¹, m², m³ and m⁴ are each independently 0, 1 or 2; and Q²is C₃-C₈ cycloalkyl optionally substituted with C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ heteroalkyl, F, Cl, Br, I, OH, SH, NH₂, CN or N₃.
 21. Acompound selected from Table I, Table II, or Table III.
 22. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier, diluent or excipient.
 23. A methodof preventing, treating or lessening the severity of a disease orcondition responsive to the inhibition of a Janus kinase activity in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound of claim
 1. 24. The method of claim 23,wherein the disease or condition is asthma.
 25. The method of claim 23,wherein the Janus kinase is JAK1.